3. Squamous Cell Carcinoma
Cutaneous squamous cell carcinoma (SCC) is the second most common type of non-melanoma skin cancer, accounting for approximately 20% of skin cancers
[33][16]. Risk factors for developing SCC include advanced age, extensive sun exposure, and immunosuppression
[33][16]. Typically, most SCC lesions can be successfully treated with excision; however, some metastasize, potentially becoming life-threatening. Thus, about 75% of all deaths due to skin cancer are caused by SCC
[33][16]. The development of SCC is gradual, stemming from an uncontrolled proliferation of epidermal keratinocytes and progression through dysplasia and actinic keratosis as the tumor cells accumulate genetic mutations in genes such as
TP53,
CDKN21,
NOTCH, and
RAS [33,34][16][17]. During tumorigenesis, the cancer cells enable growth, angiogenesis, and metastasis through autocrine and paracrine signaling
[35][18]. Recent research has shown that the loss of p53, which commonly occurs in SCC tumors, allows for increased expression of type 2 Deiodinase (D2), an enzyme that activates the thyroid hormone (TH)
[36,37][19][20]. In turn, TH induces VEGF-A transcription in SCC tumor cells, fostering tumor angiogenesis, nutrient delivery, and cancer progression
[38][21].
4. Therapeutic Considerations for Skin Cancer
For both BCC and SCC, surgical excision is the preferred treatment
[54,55][22][23]. However, for advanced or metastatic non-resectable cancers, management has transitioned to an immunotherapeutic approach
[56][24]. The treatment of advanced BCC focuses on Shh inhibition, while therapy for SCC interferes with the PD-1/PD-L1 checkpoint
[57,58][25][26].
Early treatment of BCC with surgical resection is curative in most cases, but, for some patients, locally advanced or metastatic tumors can be life-threatening or, at the very least, can negatively impact a patient’s quality of life
[54][22]. Therefore, clinicians have turned to Shh pathway inhibitors such as vismodegib or sonidegib as an alternative treatment for more severe cases
[54,57][22][25]. Administration of these Shh inhibitors triggers increases in tumor-infiltrating CD8+ T cells and tumor-cell major histocompatibility complex I (MHC class I), stimulating an anti-tumoral response within the TME
[57][25]. The ERIVANCE trial, studying the efficacy of vismodegib in advanced BCC, showed overall response rates of 48.5% in metastatic cohorts and 60.3% in locally advanced patients
[59][27]. However, that still leaves many cases of BCC that are unresponsive to this treatment, despite its seemingly beneficial immunologic effects
[57][25]. Recent studies have shown that vismodegib-resistant tumor cells transform their cell identity toward a mesenchymal stem cell-like profile, becoming resistant to Shh pathway inhibitors but providing a potential target for therapy
[14].
For patients with SCC, surgical excision is the treatment modality of choice; however, for patients with increased risks of local recurrence, perineural spread, and metastasis, immunotherapy with cemiplimab, pembrolizumab, or nivolumab have been considered
[55,58][23][26]. These drugs are PD-1 inhibitors, which inhibit the PD-1/PD-L1 immune checkpoint that typically decreases T cell functionality in the TME, suppresses the immune system, and accelerates cancer cell proliferation
[58,60][26][28]. Therefore, treatment with these immunotherapy agents increases the volume of cytotoxic CD8+ T cells in the TME, allowing for tumor cell destruction
[58][26]. In advanced-stage patients who responded to neoadjuvant cemiplimab, the drug had an overwhelming response, with many patients achieving complete pathologic responses
[61][29]. The most suitable combination of this drug with other treatment modalities such as surgery and radiation, the clinical meaning of a pathologic complete response after immunotherapy, and the need for further treatment are still being explored. However, similar to the treatment of BCC with vismodegib, SCC therapy with cemiplimab achieved an objective response rate of approximately 50% of patients
[62][30]. Therefore, further research must be conducted to determine more effective treatment methods for advanced SCC.
A better understanding of the TME provides many potential sites for intervention. For example, finding a way to polarize TAMs toward their M1 anti-tumorigenic phenotypes through immune modulation mechanisms may be a nonsurgical method to treat advanced BCC in the future
[24][31]. Likewise, TANs in SCC could be polarized more toward the N1 phenotype through the inhibition of TGF-β in the TME
[52][32]. As new research further explores the intricacies of the TME of BCC and SCC, there will be more opportunities to develop targeted therapies to treat advanced cancers.
Research into TME therapeutic targets is ongoing. Lu et al. discovered that the overexpression of the brain-derived neurotrophic factor (BDNF) and its p75 pan-neurotrophin receptor could induce BCC tumor cell death by stimulating M1 macrophages and T cell recruitment on a mouse model, providing a potential therapeutic intervention for Shh inhibitor-resistant tumors
[63][33]. Moreover, by studying cancers with similar TME profiles to that of BCC, researchers have begun investigating the use of therapies for other cancers, such as kidney chromophobe cancers or myxofibrosarcoma, in treating advanced BCC. For example, Zhang et al. suggested targeting the RB pathway, as one would treat myxofibrosarcoma to modulate the TME contained within the BCC fibromyxoid stroma, rendering it less suitable for tumor growth
[64][34].
WThe researche
rs conducted a search on clinicaltrials.gov using the search terms “Skin Cancer, Non-Melanomta”, “SCC”, and “BCC” to identify clinical trials targeting components of the TME. Some of these innovative trials include a few institutions who are attempting to use genetically modified viruses to enhance host immune responses against BCC and cutaneous SCC lesions. Researchers are studying the type I herpes simplex virus genetically modified to preferentially replicate in tumor cells talimogene laherparepvec (T-VEC) because it can be injected directly into tumors to enhance antigen presentation by DCs, promoting an anti-oncogenic immune response [ID: NCT03458117, NCT02978625, NCT04163952]
[65][35]. Other institutions are researching similar biologics including Imvamune, a modified smallpox vaccine, and IFx-Hu2.0, an immunomodulatory agent that triggers innate and adaptive immune responses in non-melanoma skin cancer tumors [ID: NCT04410874, NCT04160065]. Specifically for treating cutaneous SCC, a non-coding RNA called CV8102 has been developed to mimic a viral infection of the tumor, which serves to recruit and activate APCs and, subsequently, T cells to kill tumor cells at the site of injection [ID: NCT03291002]. Thus, a deeper understanding of the cellular players and interactions within the TME has allowed for the development of novel immunotherapies.