RESUMEN
Immune checkpoint blockade (ICB) approaches have changed the therapeutic landscape for many tumor types. However, half of cutaneous squamous cell carcinoma (cSCC) patients remain unresponsive or develop resistance. Here, we show that, during cSCC progression in male mice, cancer cells acquire epithelial/mesenchymal plasticity and change their immune checkpoint (IC) ligand profile according to their features, dictating the IC pathways involved in immune evasion. Epithelial cancer cells, through the PD-1/PD-L1 pathway, and mesenchymal cancer cells, through the CTLA-4/CD80 and TIGIT/CD155 pathways, differentially block antitumor immune responses and determine the response to ICB therapies. Accordingly, the anti-PD-L1/TIGIT combination is the most effective strategy for blocking the growth of cSCCs that contain both epithelial and mesenchymal cancer cells. The expression of E-cadherin/Vimentin/CD80/CD155 proteins in cSCC, HNSCC and melanoma patient samples predicts response to anti-PD-1/PD-L1 therapy. Collectively, our findings indicate that the selection of ICB therapies should take into account the epithelial/mesenchymal features of cancer cells.
Asunto(s)
Antígeno B7-H1 , Carcinoma de Células Escamosas , Plasticidad de la Célula , Transición Epitelial-Mesenquimal , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Neoplasias Cutáneas , Animales , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapia , Neoplasias Cutáneas/tratamiento farmacológico , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Ratones , Humanos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inhibidores , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Masculino , Inmunoterapia/métodos , Transición Epitelial-Mesenquimal/inmunología , Plasticidad de la Célula/efectos de los fármacos , Línea Celular Tumoral , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/metabolismo , Antígeno CTLA-4/inmunología , Receptores Virales/metabolismo , Receptores Virales/genética , Antígeno B7-1/metabolismo , Receptores Inmunológicos/metabolismoRESUMEN
INTRODUCTION: There is a need to improve the outcomes of patients with head and neck squamous cell carcinoma (HNSCC) and nasopharyngeal carcinoma (NPC), especially in recurrent unresectable and metastatic (R/M) setting. Antibody-drug conjugates (ADC) and bispecific antibodies (BsAb) may deliver promising results. METHODS: We conducted a systematic literature review to identify ADC and BsAb clinical trials, involving patients with HNSCC and NPC, from database creation to December 2023. We reported trial characteristics, overall response rate (ORR), overall survival (OS), and grade ≥ 3 treatment-related adverse events (trAEs). RESULTS: 23 trials (65 % phase I) were found, involving 540 R/M patients (355 [20trials] HNSCC and 185 [5trials] NPC). There were 13 ADC (n = 343) and 10 BsAb (n = 197) trials. 96 % patients were refractory to standard of care treatments. ORR ranged from 0 to 100 %, with the highest ORR for GEN1042 plus chemoimmunotherapy. ORRs for monotherapies were 47 % for ADC, and 0-37 % for BsAb. MRG003 reached in HNSCC 43 % and NPC 47 %. BL-B01D1 54 % in NPC. Longest median OS was seen with MRG003 and KN046. Grade ≥ 3 trAEs were 28-60 % in ADC trials, and 3-33 % BsAb. Grade ≥ 3 myelosuppressive trAEs were typically seen in 8 ADC trials, while 4 BsAb showed infusion-related reactions (IRR). Four treatment-related deaths were reported (1 pneumonitis), all ADC trials. CONCLUSION: ADC and BsAb antibodies show promise in R/M HNSCC and NPC. Results are premature by small sample sizes and lack of control arm. ADC mainly caused myelosuppression and a pneumonitis case, and BsAb IRR. Further research is warranted in this setting.