Abstract 3864: Role of NK/TAM cross-talk on T-CD8+ recruitment and efficacy of chemoimmunotherapy and MEKi combination in "cold" tumors
Authors: Nuttin Lisa , Latour Charlène , Revy Solène , Aucagne Romain , Lalle Guilhem , Ghiringhelli François , Limagne Emeric 
Published: March 2024

Abstract
In patients with non-small cell lung cancer (NSCLC), double platinum-based chemotherapy (cisplatin or carboplatin and pemetrexed) combined with the anti-PD-1 antibody has shown significant clinical benefit and has become the standard of care. In the context of so-called "cold" tumors, the immunogenic capacities of chemotherapies increase danger signals (type I IFNs, CXCL9/10) and favor both infiltration of NK/T-CD8+ cells and response to anti-PD-1. Despite the therapeutic progress represented by this new combination, some patients have limited benefit from chemo-immunotherapy, suggesting that in these patients, the immunogenic capacities of chemotherapy are limited. Recently, we were able to show that KRAS oncogene signaling restricts the ability of the cisplatin/pemetrexed doublet to induce the chemokine CXCL10, lymphocyte recruitment and sensitize to PD-L1 blockade. Thus, the addition of a MEK inhibitor (MEKi) to the chemo-immunotherapy combination restores an immunogenic signal through CXCL10, enabling T-CD8+ to infiltrate the tumor more extensively, making it more sensitive to immunotherapy. Here, we unravel the essential role of NK cells in the immunological and antitumoral effect of chemo-immunotherapy plus MEKi combination in the LLC1 preclinical lung cancer model. We showed that chemo/MEKi combination favors NK cell recruitment and activation in tumor bed through both CXCL10 and NKG2D-ligand (Rae1, Mult1). Then, IFNγ-producing NK cells trigger tumor associated macrophage switch from M2 toward M1 phenotype and amplify T-CD8+ cells recruitment through CXCL9 production by macrophages. Thus, NK cell depletion, CXCR3, CXCL9 or NKG2D-neutralization restrained chemo/MEKi therapeutic efficacy. However, IFNγ also triggers NKG2A-ligand expression (Qa-1b, HLA-E in human) which restrained NK cell activation and CD8+ T cell recruitment. Thus reducing the NKG2A pathway, by using Qa-1b-/- LLC1 cells, enhances chemo-immunotherapy/MEKi anti-tumor efficacy. Similar results were obtained in preclinical “cold” CT26 colon cancer model treated by chemo-immunotherapy. Our results underline a new role for NK cell activation to trigger TAM2/TAM1 switch, CXCL9 expression and amplify CD8 T cell recruitment in “cold” tumor. In a context of resistance to chemo-immunotherapy, MEKi or ICI targeting NK cells could be an interesting way to amplify the anti-tumor immune response by modulating both TAMs biology and the recruitment of CD8+ T cells.
Citation Format: Lisa Nuttin, Charlène Latour, Solène Revy, Romain Aucagne, Guilhem Lalle, François Ghiringhelli, Emeric Limagne. Role of NK/TAM cross-talk on T-CD8+ recruitment and efficacy of chemoimmunotherapy and MEKi combination in "cold" tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3864.