Abstract B029: Tumor immune microenvironment determinants of response to lenvatinib and a PD-1 blockade in clear cell renal cell carcinoma
Authors: Vuong Lynda , Kuo Fengshen , Jiang Hui , Mascareno Eduardo A. , Rappold Phillip , Sabio Erich , Weiss Kate , Cornish Andrew , Reese Stephen , Adlesic Mojca , Solit David , Frew Ian , Akin Oguz , Chen Yingbei , Li Ming O. , Chan Timothy A. , Hakimi Ari A. 
Published: August 2023

Abstract
Combinations of ICB and anti-angiogenesis tyrosine kinase inhibitors (aATKIs) are the mainstay of metastatic ccRCC front line treatment, but heterogenous responses and lack of biomarkers strongly emphasizes the need to understand RCC-specific mechanisms of effective anti-tumor immunity in the treatment context. Although prior work highlights the critical role and heterogeneity of tumor associated macrophages (TAMs) in prognosis and response to ICB and aATKIs, TAM modulation has yet to be tested in RCC. We therefore assessed the impact of TAM depletion using a CSF1R inhibitor (BLZ945) on drug sensitivity in a genetically engineered mouse model (GEMM) of ccRCC, comprising inducible kidney-specific Vhl, p53 and Rb1 deletion (KVpR). Following tamoxifen-induced driver gene deletion, male mice were monitored for multifocal kidney tumor development from 25-52 weeks using micro-ultrasound. Tumors were confirmed and their volumes tracked by weekly MRI imaging. Mice were randomized to receive either no treatment, or single agent Lenvatinib, aPD-1, BLZ945 or combinations. A total of 299 tumors from 86 mice were included in the final analysis. A total of 37 tumors across treatment arms were collected at responsive or resistant time points, for profiling by single cell RNA sequencing (scRNAseq; 10X) to elucidate the underlying mechanisms of response. Surprisingly, we found that TAM depletion negated an effective aPD-1 response. ScRNAseq analysis suggests that this is due to selective depletion of antigen presenting TAMs, and a subsequent striking loss of CD8 T cell presence. Since dendritic cells were not depleted by BLZ945, this suggests that intratumor T cell activation by TAMs is a major mechanism of aPD-1 therapeutic targeting. Beyond enhancement of a conventional CD8 T cell response induced by Lenvatinib and aPD-1, we also highlight the potential roles of type 3 immunity in RCC immune surveillance. Our results emphasize the deleterious impact of pan-macrophage depletion approaches that are currently being deployed in clinical trials with ICB, and highlight the importance of lesser studied immune cell types as promising avenues for future validation as novel biomarkers and targets.
Citation Format: Lynda Vuong, Fengshen Kuo, Hui Jiang, Eduardo A. Mascareno, Phillip Rappold, Erich Sabio, Kate Weiss, Andrew Cornish, Stephen Reese, Mojca Adlesic, David Solit, Ian Frew, Oguz Akin, Yingbei Chen, Ming O. Li, Timothy A. Chan, Ari A. Hakimi. Tumor immune microenvironment determinants of response to lenvatinib and a PD-1 blockade in clear cell renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr B029.