HLA-I levels correlate with survival outcomes in response to immune checkpoint inhibitors in non-small cell lung cancer.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) have provided a breakthrough in the treatment of non-small cell lung cancer (NSCLC) patients, but only some patients benefit substantively. Identifying definitive predictive biomarkers could overcome this limitation. MATERIALS AND METHODS: We selected 146 metastatic NSCLC patients treated with anti-PD-(L)1. Immunohistochemistry of HLA-I, PD-L1 and CD73 was performed in 122 tumor biopsies at diagnosis. The association with patients, tumor parameters, and the predictive value to ICI treatment were determined. RESULTS: In our cohort, 42 %, 25 %, and 21 % of the tumors exhibited high levels of HLA-I, PD-L1, and CD73, respectively. Lung adenocarcinomas displayed elevated CD73 levels, compared with lung squamous cell carcinomas (P = 0.026). High PD-L1 was significantly correlated with high levels of HLA-I (P = 0.005) and of CD73 (P = 0.025). Patients with high-level HLA-I tumors exhibited more favorable clinical outcomes following ICI, with a median overall survival of 30.7 months (95 % confidence interval [CI]: 18.3 months-not reached), compared with 18.2 months (95 % CI: 12.4-25.2 months) in patients with low-level HLA-I tumors (P = 0.016). The median progression-free survival (PFS) for patients with high-level HLA-I tumors was 18.5 months (95 % CI: 11.1-57.1 months), longer than patients with low-level HLA-I tumors, whose median PFS was 9.2 months (95 % CI: 7.2-11.9 months) (P = 0.006). In a multivariable analysis, high-level HLA-I was independently associated with lower risk of progression to ICI (HR = 0.46, 95 % CI 0.24-0.87; P = 0.018). CONCLUSIONS: High-level HLA-I were associated with better clinical outcomes to ICI in our cohort of NSCLC patients. Therefore, further investigations are warranted to refine this biomarker and validate its efficacy in prospective and larger set of patients.

Medicina de precisión en inmunoterapia y cáncer de pulmón / Precision medicine in immunotherapy and lung cancer

La incorporación a la práctica clínica de los fármacos que inhiben el punto de control inmunitario (ICI, del inglés immunocheckpoint inhibitors), como los anticuerpos monoclonales que se dirigen al antígeno 4 asociado a linfocitos T citotóxico (CTLA-4) y la proteína de muerte celular programada 1 (PD1) y su ligando (PD-L1), han representado un gran avance en el tratamiento de distintos tipos de cáncer, especialmente el cáncer de pulmón de célula no pequeña (CPCNP), el subtipo de cáncer de pulmón más frecuente. A pesar de que la inmunoterapia se ha convertido en el estándar de tratamiento en varios tipos de cáncer, ya sea sola o en combinación con quimioterapia, no todos los pacientes responden a estos fármacos. Algunos de ellos incluso sufren de una acusada progresión tumoral durante el tratamiento. Es por ello por lo que existe la necesidad clínica de identificar biomarcadores predictivos que presenten una elevada sensitividad y especificidad. En el caso de los tratamientos basados en PD1/PD-L1, hoy en día se utiliza como biomarcador los niveles tumorales de PD-L1, aunque su capacidad de predecir la respuesta a estas nuevas drogas es ciertamente limitada. En este trabajo de revisión se describirá lo que se conoce actualmente acerca de la interacción dinámica entre la célula tumoral y el sistema inmunológico durante la carcinogénesis, haciendo especial énfasis en la descripción de las estrategias moleculares que utiliza la célula tumoral para evitar una eficiente respuesta antitumoral por el sistema inmune del huésped. Se hará hincapié en aquellas alteraciones génicas deletéreas en componentes del complejo mayor de histocompatibilidad y en moléculas mediadoras de la respuesta a interferón gamma (IFNg). (AU)

The inclusion into cancer clinical settings of the so-called immune-checkpoint inhibitors (ICIs), such as those targeting the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1) and its ligand (PD-L1), has represented a breakthrough in cancer treatment, especially in non-small cell lung cancer (NSCLC), the most common type of lung cancer. Despite becoming the standard of care in some cancers, either alone or in combination with chemotherapy, a proportion ofpatients do not respond while others progress during treatment. Therefore, there is a clinical need to identify accurate predictive biomarkers and to develop novel therapeutic strategies based on ICIs. The current marker used to predict response to ICI treatments are the levels of PD-L1, but this is a quite inaccurate biomarker. In this review it will be described what is currently known about the dynamic interaction between the cancer cell and the immune system during carcinogenesis, with a particular focus on the description of the functions and alterations that preclude the host immunoresponse in cancer. We emphasize the deleterious gene alterations in components of the major histocompatibility complex and of the response to IFNγ. The role of other gene alterations, such as those of common oncogenes and tumor suppressors, and of the epigenetic alterations will also be discussed, in detail. Finally, we discuss the potential use of the tumor’s genetic profile to predict response to ICIs. (AU)