High relative ratio of adaptive to innate tumor infiltrating immune cells predicts for immunotherapy response and associates with improved prognosis

Abstract Immunotherapy has revolutionized cancer treatment. However, not all cancer patients benefit, and current stratification strategies based primarily on PD1 status and mutation burden is far from perfect. We hypothesized that high activation of an innate response relative to the adaptive response may prevent proper tumor neoantigen identification and decrease the specific anticancer response, both in the presence and absence of immunotherapy. To investigate this, we defined signatures of innate and adaptive immune response from bulk tumor RNAseq data, and compared the relative activation of both immune compartments. We acquired publicly available transcriptomic data from both primary and metastatic cancer cohorts from the Cancer Genome Atlas (TCGA), the Hartwig Medical Foundation (HMF), and from a recently published cohort of metastatic bladder cancer patients treated with immunotherapy. To analyse adaptive and innate immune infiltration into bulk tumors, we developed a model to estimate the overall level of innate and adaptive immune cells, based on previously published definitions. From these, we defined the overall adaptive-to-innate immune ratio (AIR) score as the ratio of average gene expression of genes associated with the adaptive and innate immune system, respectively. Pan-cancer analysis of primary tumor samples from TCGA showed improved progression free survival in patients with an AIR score above median (P < 0.0001), and that patients without a progression event had overall a significantly higher AIR score (P < 2*10-16). Interestingly, we found that the association was different for males and females for several cancer types, indicating a potential a gender bias in activation of the immune response (female P < 2*10-16, male P = 1.1*10-14). For patients with metastatic disease, we found that responders to immunotherapy have a significantly higher AIR score than non-responders in HMF (female P = 0.0037, male P = 2.5*10-5) and a significantly higher score in complete responders in a separate metastatic bladder cancer dataset where response was primarily observed in male patients (P = 0.015). Furthermore, histological analysis revealed that tumors which had a significantly higher AIR score, were highly infiltrated by immune cells (P = 0.00047), providing orthogonal support that the AIR score associates with an anti-tumor immune response. Overall, the adaptive-to-innate immune ratio seems to define separate states of immune activation, likely linked to fundamental immunological reactions to cancer. Our score associates with both improved prognosis and improved response to immunotherapy, demonstrating potential use in patient stratification. Furthermore, by demonstrating a significant difference between males and females that associates with response, we highlight an important gender bias which likely has direct clinical relevance. Citation Format: Johanne Ahrenfeldt, Andreas B. Østergaard, Ditte S. Christensen, Judit Kisistók, Mateo Sokač, Nicolai J. Birkbak. High relative ratio of adaptive to innate tumor infiltrating immune cells predicts for immunotherapy response and associates with improved prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2724.