Suppression of Major Histocompatibility Complex (MHC) Class I and II Mediates Resistance to Anti-PD-1 in Lung Adenocarcinoma Tumors That Can Be Overcome by Radiation Therapy

ALBA M GÜERCI

Ciudad Autónoma de Buenos Aires

Congreso; II BEST of ASTRO en Argentina; 2017

Sociedad Argentina de Terapia Radiante Oncológica:SATRO

Abstract 201AUTORES Y FILIACIONJ. W. Welsh5; X. Wang1, J. E. Schoenhals1, D. R. Valdecanas1, A. Li1, H. Ye2, F. Zhang3, M. Tang4, C. Tang5, C. G. Liu6, X. Liu6, R. U. Komaki5, D. R. Gomez5, J. Y. Chang5, M. A. Cortez1, and 1Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 2Department of Experimental Radiation Oncology, MD Anderson Cancer Center, Houston, TX, 3Department of Pathology The University of Texas MD Anderson Cancer Center, Houston, TX, 4Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 5Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 6Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TXPurpose/Objective(s): PD-1/PD-L1 blockage therapy, given as single agent have produced objective response rates ranging from 15 % to 25% in patients-with chemotherapy refractory non-small-cell-lung-carcinoma-(NSCLC). Nevertheless, large proportions of patients do not respond to anti-PD-1/PD-L1 immunotherapies. Therefore, we sought to investigate the mechanisms of nonresponses and potential strategies to overcome resistance. Here we generated an anti-PD-1-resistant preclinical tumor model with which to identify mechanisms of resistance, which should provide novel insights to expand the benefit of immunotherapies. Materials/Methods: This model was generated by inoculating the murine lung cancer cell line 344SQ (containing p53R172H-g/+K -rasLA1/+ mutations) into syngeneic 129Sv/ev mice, which were then given 4-5 doses of anti-mouse PD-1 antibody(10 mg/kg). The anti-PD-1 resistant tumor model was successfully generated after sequential in vivo passage of a nonresponsive tumor with ongoing anti-PD-1 treatment. For the combined radiation plus anti-PD-1 therapy studies, the first dose of anti-PD-1 (10 mg/kg) was given on the same day of first fraction of radiation (12G in 3 fractions) and continued for additional 3-4 doses. For experiments involving blockade of type I IFN signaling, anti-mouse IFNAR-1 antibody was injected daily for 14 days, starting on the day of first dose of anti-PD-1. For studying the growth rate of the tumor mass, the length (L) and width (W) of tumors were measured with calipers. Tumor volume (V) was calculated as: V=W2 x L/2. The unpaired Student t test was used for analysis of most data except that the tumor growth curve was analyzed by multiple t tests for each time points. All reported P values are two-sided and were declared as significant at the level of 5%. Results: PD-L1 expression was not different in the resistant vs. parental tumor cells. Microarray and flow cytometry studies demonstrated that genes in the antigen presentation pathway, including major histocompatibility complex (MHC) class I and II, were significantly downregulated in the anti-PD-1-resistant tumors compared with parental tumors. Resistant tumors also showed fewer CD8+ and CD4+ tumor -infiltrating lymphocytes and reduced production of interferon (IFN)γ. Local tumor radiotherapy induced IFNγ production, which in turn induced MHC class I expression on both parental and resistant tumor cells and restored the resistant tumor to anti -PD1 response. Blockade of type I IFN signaling abolished the effect of radiation on sensitization of anti-PD-1 response. Conclusion: We discovered a novel mechanism of PD-1 resistance and demonstrated radiation can be used to overcome such resistance. Our findings suggest that the poor efficacy of anti-PD1 as an immune checkpoint therapy in most patients might be accentuated greatly by adjuvant radiotherapy, thereby broadening its useful application against melanoma and lung cancers where robust but relatively infrequent responses have been documented.