Immunotherapy for locally advanced and metastatic basal cell carcinoma: a narrative review

Introduction

Basal cell carcinoma (BCC), also called basal cell epithelioma, derives from the hair follicle and interfollicular epidermis (1). BCC is more common in the elderly, with an increasing incidence, but it has been found in younger people recently (2). Usually, BCC is seen at the head and neck, where the skin is always exposed to the ultraviolet. The pathogenesis of BCC is not very definite. The hedgehog pathway is a highly conserved signaling pathway involved in stem cell maintenance, organ generation, tissue repair, and regeneration, and its abnormal activation is considered to be the main pathogenesis (3). Tissue biopsy is the gold standard to confirm BCC, which can be divided into various subtypes due to its histopathological performances, such as nodular type, superficial type, infiltrative type, morpheaform type, pigmented type, and fibroepithelial type (4). Although BCC is characterized by low metastatic potential, it has a high recurrent rate and can cause local damage. Based on its possible risk of recurrence and metastasis, BCC can be classified as a high-risk or low-risk type (5). The dermatologist will schedule the appropriate treatment for the patient based on the subtype and location of the BCC, the patient’s physical condition, and the patient’s wishes. Surgery is the most common option for the disease, including conventional standard surgery and Mohs surgery. In addition, radiotherapy, photodynamic therapy, electric drying, curettage, etc. can also be used as treatment options (6). For refractory BCC such as metastatic BCC (mBCC) and locally advanced BCC (laBCC), which has an inferior prognosis, it is necessary to take systematic therapy. It has been noted that the median survival and 5-year survival rate of refractory BCC are 8–14 months and 10%, respectively (7). Hedgehog pathway inhibitor (HHI) is the first option for refractory BCC. Vismodegib and sonidegib have been approved for the treatment of laBCC, and vismodegib is also an approved treatment for mBCC (8). With the in-depth understanding of BCC and related research on immunotherapy, there are some new choices for patients who fail HHI therapy or who cannot tolerate the treatment. This review aims to summarize the characteristics of BCC immune microenvironment, biomarkers of BCC, and current immunotherapy for laBCC and mBCC. We present this article in accordance with the Narrative Review reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-742/rc).

Methods

We searched literature in PubMed database and Web of Science and considered all study types written in English from 2013 to 2024. The search methodology is summarized in Table 1.

Theoretical basis of immunotherapy

Immunotherapy is an approach to treat diseases by modulating patients’ immune systems, which includes immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR)-T cell therapy, vaccination, cytokines, and adoptive T-cell therapy. In 1891, William Bradley Coley was the first one to take advantage of the immune system to treat bone carcinoma and he was called the Father of Immunotherapy (9). After hundreds of years of research, with a better understanding of the immune system, immunotherapy has attempted to treat a variety of tumors, such as melanoma, skin squamous cell carcinoma, non-small cell lung cancer, liver cancer, and so on (10-12).

BCC immune microenvironment

Tumor-infiltrating lymphocyte (TIL)

The TILs in the immune microenvironment of BCC include several kinds of types, and regulatory T cells (T-regs) are predominant. Transcription factor forkhead box P3 (FOXP3) expresses on T-regs, regulating the suppressive function of T-regs. Compared with normal skin tissue, high expression of FOXP3 is observed in BCC and peritumoral skin. In addition, the expression of transforming growth factor-β (TGF-β) is highest in the peritumoral skin (13). Previous study has demonstrated the immunosuppressive capabilities of T-regs, which are mediated through the secretion of cytokines, including TGF-β (14). However, a recent study points out that T-regs may have anti-tumor capabilities (15).

Cancer-associated fibroblast (CAF)

The fibroblasts involved in tumorigenesis and growth are called CAFs. Expression of CAF markers including prolyl-4-hydroxylase, platelet-derived growth factor receptor β, and fibroblast activating protein α increases in BCC. And in BCC, the expression of CAF-related chemokines (including CXCL12, CCL17, CCL18, CCL22, CCL25, and IL6) is also increased (16). CAFs expressing epithelial-mesenchymal transition-related markers in BCC may contribute to the progression of BCC (17).

Tumor-associated macrophage (TAM)

TAMs are also an important type of immune cell in the immune microenvironment of BCC, and there are two types, M1 and M2. M1 plays a role in the anti-tumor response, while M2 promotes tumor progression. Both two types have been observed in BCC (18). Jiang et al. concluded that TAM may contribute to the characteristics and clinical behaviors of BCC by comparing TAM density and polarization state between BCC and squamous cell carcinoma. And tumor-derived lactic acid may influence the polarization of TAM (19).

In summary, tumor cells, immune cells, and immune molecules collectively constitute the tumor immune microenvironment. Immune cells can directly interact with tumor cells or secrete cytokines to indirectly act on tumor cells, which is a key link in tumor development. Immune cells can be taken as the central link in the immunotherapy of BCC, focusing on both enhancing the anti-tumor effect of immune cells and blocking the tumor-promoting effect of immune cells. For example, the pro-tumorigenic effects of T-regs are inhibited by blocking FOXP3 or by exogenously administering drugs that compete for the TGF-β receptor, or the killing effects of immune cells, such as M1, are enhanced for the treatment of BCC. More studies are needed in the future to explore the possibilities of these ideas.

Biomarkers

Sex determining region Y (SRY)-box 2 (SOX2)

SOX2 is a member of the high mobility group box family associated with SRY. SOX2 does not express in normal skin, but overexpresses in some tumors including BCC (20). Previous study found that SOX2 can influence tumorigenesis through serine-arginine protein kinase 1 (SRPK1)-mediated phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway and SOX2 is associated with migration and invasion of BCC (21). Therefore, SOX2 may be able to predict the prognosis of BCC as a kind of biomarker. On the other hand, blocking the SOX2 may be used to treat BCC, especially those with high expression of SOX2. Targeted therapy of SOX2 is being actively explored, with studies attempting to inhibit the function of SOX2 through various methods, including the use of artificial transcription factors, peptide ligands, and small molecule inhibitors, among others (22). The detailed mechanism of SOX2 in BCC immunity needs to be further explored in the future to provide more strategies for immunotherapy of BCC.

Matrix metalloproteinase (MMP)

MMPs are members of the metzincin protease superfamily of zinc-endopeptidases produced by tumor cells and normal cells and have many kinds of subtypes expressed in different tumors (23). MMPs participate in the degradation of extracellular matrix components and neovascularization so that they can promote metastasis and progress of cancer (24). Manola et al. found MMP-2 and MMP-9 expression in BCC at a high level (25). Importantly, Goździalska et al. found that the expression of MMP-9 was significantly higher in infiltrative BCC than in nodular BCC, which may be useful in predicting the prognosis of BCC (26). Ciążyńska et al. found that MMP-1, MMP-3, and MMP-8 were also overexpressed in nodular BCC (27). In addition to MMPs in the extracellular matrix, there are endogenous inhibitors of MMPs called tissue inhibitors of metalloproteinases (TIMPs) (28). When the two are expressed in an unbalanced manner, tumors may form. Exogenous MMP inhibitors may be able to prevent the development of tumors by inhibiting overexpressed MMPs. The MMPs include many types, and broad-spectrum MMP inhibitors are less selective and can suffer from low bioavailability and safety issues. The selection of specific MMP inhibitors based on the type of MMPs highly expressed in the tumor is particularly important for achieving good efficacy. A number of specific MMP inhibitors are currently been exploring (29). It is hoped that in the future, specific MMP inhibitors can be selected to treat BCC based on the type of MMP highly expressed in BCC.

Tumor mutation burden (TMB)

TMB is defined as the number of somatic, coding, base substitution, and indole mutations per megabase (m/mb) of the genome. Twenty m/mb or greater is considered to be a high TMB. High TMB has been detected in both laBCC and mBCC (30). Goodman et al. discovered that the TMB (m/mb) median is 90 (range, 3–103) for the BCCs in contrast to 4 (range, 1–860) for 1,637 cancers other than BCC, and a statistically significant difference exists (31). The patients with high TMB show a favorable response to programmed death receptor 1 (PD-1) inhibitors, suggesting that high TMB is beneficial for predicting patients' therapeutic response to PD-1 inhibitors (31). And an mBCC patient with a high TMB has achieved a complete response with pembrolizumab (32).

In addition to the above three, cyclooxygenase-2 (33) and eukaryotic initiation factor 4E (34) also were found at a high level in BCC. And Huang et al. even found that differentiation-related SOSTDC1 + IGFBP5 + CTSV + MB1 and EMT-related TNC + SFRP1 + CHGA + MB2, two subtypes of malignant basal cells, may be helpful in predicting the malignancy and prognosis of infiltrative BCC (35). However, more studies about the expression and mechanism of these biomarkers are needed to validate their clinical value.

Immune checkpoints

PD-1 and programmed death ligand 1 (PD-L1)

PD-1 gene is a CD28 family member, which is a member of the immunoglobulin gene superfamily. Both PD-L1 and programmed death ligand 2 (PD-L2) are ligands of PD-1 and PD-L1 is the primary ligand that is upregulated on tumor cells and immune cells within the tumor microenvironment (36). By upregulating PD-L1 on antigen-specific CD8⁺ T cells and its connection to PD-1, tumor tissue can restrain host immune response and lead to T cell depletion and apoptosis (37).

Lipson et al. collected 40 specimens of locally aggressive or recurrent BCC and immunohistochemical staining of these specimens was performed. The expression of PD-1 was detected on lymphocytes of each case, while the expression of PD-L1 was detected on TILs, TAMs, and tumor cells (38). Interestingly, there was no expression of PD-L1 in BCCs, which are not at the head and neck location (39,40). This difference may be related to ultraviolet exposure and BCC progression. The expression level of PD-L1 in different BCC subtypes was different, and the expression of PD-L1 in nodular BCC was the highest (41). The study of Chang et al. showed that compared with untreated BCC, the expression of PD-L1 on tumor cells and TILs of recurrent BCC was significantly increased, so it was believed that the expression level of PD-L1 might be related to prior treatment response (42).

Cytotoxic T-lymphocyte antigen 4 (CTLA-4)

CTLA-4, expressed on T-regs, interacts with antigen-presenting cells to inhibit T-cell activation. The study of Sławińska et al. demonstrated that the multiple BCC susceptibility may be associated with CTLA-4 rs5742909 polymorphism, but CTLA-4 polymorphisms do not affect the BCC susceptibility (43). Lymphocyte activation gene 3 (LAG-3) is an inhibitory coreceptor and has an effect on autoimmunity, anti-infection immunity, and tumor immunity (44). Lajoie et al. (45) compared the expression of CTLA-4 and LAG-3 in nodular and invasive BCC, and found that the expression of CTLA-4 was higher in invasive BCC. However, there was no significant difference in the expression of LAG-3 between the two groups.

B7-H3 (CD276)

B7-H3 is an immune checkpoint molecule that is underexpressed in most normal tissue cells and overexpressed in different tumor cells, such as melanoma, osteosarcoma, and Ewing’s sarcoma (46). And as a member of the B7 family, also named CD276, B7-H3 participated in the progression and invasion of tumors (46). Immunohistochemical staining showed 80% positivity of B7-H3 in a case of BCC (47). However, the mechanism of B7-H3 in the progression of BCC is not clear. It has been shown that tumor cells may inhibit T cell proliferation by expressing B7-H3. More studies about the mechanism of B7-H3 in the future may be helpful to the therapy of refractory BCC.

In addition to the increased immune checkpoint proteins on cells, the soluble immune checkpoint molecules in BCC are also increased. Compared with healthy controls, plasma concentrations of soluble PD-1, PD-L1, CTLA-4, LAG-3, and mucin-containing domain 3 were significantly higher in BCC patients (48). The change of soluble immune checkpoint molecules in the plasma may be helpful in choosing treatment methods and predicting the efficacy of treatment.

Current clinical application of immunotherapy in BCC

PD-1/PD-L1 inhibition therapy

Cemiplimab

Cemiplimab is a highly potent, fully human immunoglobulin G4 (IgG4) monoclonal antibody directed against PD1. On February 9, 2021, cemiplimab was approved for BCC patients who are not appropriate to have HHIs by the United States (US) Food and Drug Administration (49). There is a phase 2, non-randomized, multicenter research of cemiplimab in patients with mBCC who didn’t benefit from HHI therapy. The interim analysis from Lewis et al. indicated that 6 of 28 patients had a partial response and overall survival was 25.7 months (50). In an open-label, multicenter, phase 2 trial about mBCC and laBCC, patients received cemiplimab 350 mg intravenously (IV) every 3 weeks. The study showed that 25% of patients had a partial response and 6% of patients had a complete response (51). The result of a recent study has also shown that cemiplimab has an antitumor effect on mBCC. The objective response rate (ORR) per independent central review (ICR) was 22% (52).

Pembrolizumab

Pembrolizumab is also a humanized IgG4 monoclonal antibody inhibiting PD-1. A 62-year-old woman with recurrent and lung mBCC received pembrolizumab for four cycles after failing HHIs therapy. The patient got a lung lesion progression, and the BCC was surgically excised. The immunohistochemical staining of pulmonary tumor tissue showed a rather low expression of PD-L1 (53). A 67-year-old woman with recurrent and multiple lung mBCC who was resistant to HHIs received pembrolizumab 2 mg/kg IV every 3 weeks and had a partial response after a month of treatment. Immunohistochemical staining of the patient’s pretreatment BCC showed that PD-L1 expressed on immune cells but not tumor cells (38). A man about 50 years old with recurrent and mBCC who was resistant to HHIs was treated with pembrolizumab 2 mg/kg IV every 3 weeks. After 6 weeks of treatment, a computed tomography scan showed remission of multiple lung lesions. However, after 16 weeks of treatment, the patient had a bone metastasis. He underwent a laminectomy, and the immunohistochemical staining of the excision showed little expression of PD-L1 (54). The study of Chang et al. also concluded that pembrolizumab is active against BCC (55). Although the immunochemical staining didn’t detect the expression of PD-L1, a 77-year-old woman with laBCC obtained a partial response after seven cycles of pembrolizumab (40). As a result, there is a dispute between the efficacy of pembrolizumab and the expression of PD-L1.

Nivolumab

Nivolumab is a humanized IgG4 monoclonal antibody that combines with PD-1 and prohibits the interaction between PD-1 and its ligand. Véron et al. conducted a phase 2 basket study to estimate the efficacy and safety of nivolumab in patients with laBCC or mBCC. The final result showed that 12.5% of patients had a complete response, 18.8% of patients had a partial response, and 43.8% of patients had stable disease (56). There are also a few cases of BCC patients treated with nivolumab. A 58-year-old man with recurrent and multiple mBCC involving the axial skeleton, lungs, and liver was treated with nivolumab after prior HHIs therapy. Four months later, the patient got a near complete remission in the hepatic lesions. Amplification of PD-L1 and PD-L2 was detected (57). Interestingly, this patient developed superficial BCC in the left anterior shoulder and left chest during remission of mBCC with nivolumab. No amplification of PD-L1 and PD-L2 was detected in the skin lesion compared to the liver lesion (58). Similarly, a 78-year-old woman with metastatic non-small cell lung cancer developed a BCC located at the right ala of the nose under nivolumab 3 mg/kg every 2 weeks. The BCC of the patient was removed by surgery. But 2 months later, a new BCC was found at the same location as the previous surgical excision, and another operation was performed. Immunohistochemical staining of two BCC lesions both demonstrated very little PD-L1 expression on tumor cells and immune cells (59). The above case reports suggest that the therapeutic efficacy of nivolumab may be related to the expression of PD-L1 in BCC. Furthermore, newly developed BCCs may express less PD-L1.

Atezolizumab

Atezolizumab is a PD-L1 inhibitor. In one case report, a 72-year-old patient who suffered advanced BCC and metastatic myoinvasive urothelial carcinoma was treated with 1,200 mg of atzolizumab for 17 cycles. Stability in advanced BCC and complete remission in metastatic myoinvasive urothelial carcinoma were observed, without any adverse effects (60).

CTLA-4 inhibition therapy

Ipilimumab is a fully humanized monoclonal antibody against CTLA-4. It specifically blocks the CTLA-4 inhibitory signaling pathway, activating T lymphocytes and promoting T lymphocyte proliferation, and it can infiltrate into tumor tissues, causing cancer cell death. It indirectly plays a role in enhancing T lymphocyte-mediated immune response. Mohan et al. reported a case of an elderly man with BCC whose BCC had occasionally regressed while receiving ipilimumab for metastatic melanoma (61).

LAG-3 inhibition therapy

Relatlimab can bind to LAG-3 on T-regs, blocking immunosuppressive signals and enhancing the anti-tumor effects of immune cells. Deutsch et al. reported a patient with laBCC who experienced stable disease during and after 45 weeks of nivolumab, followed by a partial response after the addition of relatlimab. Immunohistochemical staining showed that the expression of LAG-3 increased after anti-PD-1 treatment (62).

In addition to the above published findings, there are some relevant clinical trials underway, such as NCT03889912 (evaluating safety and tolerability of cemiplimab in patients with cutaneous squamous cell carcinoma or BCC), NCT05929664 (assessing the efficacy of cemiplimab in patients with laBCC of the head and neck in the neoadjuvant, presurgical setting), NCT04679480 (evaluating efficacy and safety in patients with refractory BCC treated with a combination of anti-PD1 antibody and pulsed hedgehog inhibitor), and NCT03521830 (assessing the efficacy of nivolumab, alone or in combination with relatlimab or ipilimumab in treating patients with laBCC or mBCC).

A retrospective study has compared the efficacy and safety of ICIs and HHIs in the treatment of refractory BCC. The data has shown that they have comparable efficacy, but HHIs cause more adverse effects than ICIs (63). The clinical trial results are summarized in Table 2.

CAR-T cell therapy

CAR-T cells targeting B7-H3 had exhibited antitumor response without toxicity in solid tumors, such as ovarian cancer and neuroblastoma (64). Hu et al. first reported a case of CAR-T cell immunotherapy on BCC. The patient is a 65-year-old man suffering from recurrent and mBCC. He received three doses of CAR-T cells intratumoral injection. Partial response was observed and adverse events like redness, itching, and myalgia also occurred. Immunohistochemical staining after CAR-T cell therapy showed a decrease in the proportion of B7-H3 positive cells (47).

Vaccination

Jørgensen et al. developed a kind of vaccination called IO103, which is a highly immunogenic 19-aminoacid peptide against PD-L1 (65). And they conducted a phase IIa study administering IO103 and montanide adjuvant vaccines to patients with BCC. Six doses of the vaccine were administered every 14 days, followed by three doses every 28 days for responders. Partial response or complete response was observed in these patients with mild adverse events (66).

Other potential immunotherapies

Currently, the detailed mechanism of BCC metastasis and invasion remains unknown. A recent study found that heat shock proteins (HSPs) overexpress in BCC, particularly HSP70 family members, and demonstrated that the HSP pathway may be a potential therapeutic target for BCC (67). Besides, external pro-brain-derived neurotrophic factor treatment may be another potential therapy for BCC (68).

Conclusions

Although there are many treatments available for BCC, the efficacy of commonly used treatments for laBCC and mBCC is poor. Recurrent BCCs bring great harm to both the patient’s body and mind. The application of immunotherapy is very necessary for these patients with laBCC or mBCC. As a kind of tumor with a high mutational burden (69), immunotherapies have embodied efficacy in BCC therapy. The mechanism of drugs is shown in Figures 1,2. Cemiplimab is currently the only Food and Drug Administration-approved drug for BCC against PD-1. Current studies related to immunotherapies have been presented mainly in the form of case reports, which include anti-PD-1/PD-L1 therapy, anti-CTLA-4 therapy, CAR-T cell therapy, LAG-3 inhibition therapy and vaccination. Future studies may be able to further explore the efficacy and safety of immunotherapies by conducting animal testing with large samples and multicenter clinical trials. According to the research results reported so far, there are relatively many studies on PD-1 inhibition therapy, and most patients have partial or complete response with wild side effects (70). And PD-1 inhibition therapy may decrease the incidence of BCC (71). Different treatment methods combined with immunotherapy may be a research direction to meet the situation that complete remission cannot be achieved with isolated immunotherapy. In addition, for some complex and refractory cases, multidisciplinary consultation is necessary. Specific biomarkers may be useful for early identification of metastatic and aggressive characteristics of BCC and immune checkpoints may be useful for selection of appropriate immunotherapies to control the disease and improve prognosis. Current research about biomarkers of BCC in predicting prognosis is limited and there are no definitive results available for clinical use. Further exploration of biomarkers to predict prognosis is necessary, and the biomarkers should be detectable in pathologic specimens or blood. Early use of immunotherapy in patients who may develop refractory BCC may prevent unwanted consequences. Moreover, long-term follow-up helps to detect the possibility of recurrence early and take measures to improve quality of life.

Figure 1 Immune microenvironment of BCC. Signal 1: CD80/CD86 combines with CTLA-4 and then inhibit TIL activation; signal 2: PD-1 combines with PD-L1 and then inhibits the host immune response and results in TIL exhaustion and apoptosis. APC, antigen-presenting cell; TIL, tumor-infiltrating lymphocyte; CAF, cancer-associated fibroblast; TAM, tumor-associated macrophage; CTLA-4, cytotoxic T-lymphocyte antigen 4; LAG-3, lymphocyte activation gene 3; PD-1, programmed death receptor 1; PD-L1, programmed death ligand 1; BCC, basal cell carcinoma.

Figure 2 Targeting therapy of BCC. Signal 1: CD80/CD86 combines with CTLA-4 and then inhibit TIL activation; signal 2: PD-1 combines with PD-L1 and then inhibits the host immune response and results in TIL exhaustion and apoptosis, APC, antigen-presenting cell; TIL, tumor-infiltrating lymphocyte; CAF, cancer-associated fibroblast; TAM, tumor-associated macrophage; CTLA-4, cytotoxic T-lymphocyte antigen 4; LAG-3, lymphocyte activation gene 3; PD-1, programmed death receptor 1; PD-L1, programmed death ligand 1; CAR-T, chimeric antigen receptor-T; BCC, basal cell carcinoma.

Acknowledgments

Funding: This work was supported by the Dongguan Science and Technology of Social Development Program (No. 20211800904562).

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-742/rc

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