Immune Regulation of Lung Squamous Metastasis

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Project Summary: Lung cancer is the leading cause of cancer-related deaths in the U.S., accounting for 158,040 deaths in 2015. While targeted therapies of lung adenocarcinoma have improved overall survival, similar advances in lung squamous carcinoma (LUSC) have been stagnant. Extensive molecular profiling through the Cancer Genome Atlas (TCGA) effort revealed that LUSC tumors are highly idiosyncratic and rarely driven by solitary actionable pathways. However, the tumor microenvironment (TME), which promotes the metastasis that accounts for 90 percent of cancer-related deaths, remains an attractive target for immune-based therapies. Recently, the blockade of immune checkpoints with anti-Programed cell death protein 1 (PD1) antibodies has demonstrated remarkable therapeutic promise in LUSC patients, with about 20% of unselected patients experiencing durable responses. Thus, a more complete understanding of how the tumor microenvironment (TME) promotes LUSC will allow us to build upon these advances. Using updated TCGA data for LUSC, we have uncovered a previously unidentified subset of LUSC characterized by infiltration of inflammatory monocytes (IMs). This subset accounts for nearly half of all LUSC patients, is associated with very poor outcome, and has numerous signatures of immune evasion. Using immune-competent metastasis models of LUSC developed in our lab, we have found that the CCL2-CCR2 axis is highly associated with IM recruitment and promotion of LUSC metastasis. Although studies in other cancer types have revealed IMs differentiate into tumor-associated macrophages (TAMs), which in turn leads to increased angiogenesis and invasiveness, very little is known about the direct role of IMs on LUSC growth and metastasis. Taken together, we hypothesize that specific molecular processes (i) recruit IMs into the LUSC tumor microenvironment, which (ii) directly promotes LUSC tumor growth and development of distant metastasis, and (iii) interruption of the CCL2-CCR2 axis will therapeutically inhibit these processes. In Aim 1, we will determine and characterize the upstream molecular drivers responsible for IM recruitment into the LUSC microenvironment. In Aim 2, we will determine the direct role of IMs in promoting LUSC tumor growth and metastasis. In Aim 3, we will evaluate the therapeutic efficacy of targeting IMs in immune-competent metastasis models of LUSC, and whether this therapeutic approach is synergistic in combination with anti-PD1 immune checkpoint inhibitors. Thus, taken together, our proposal aims to uncover the molecular underpinnings that promote IM infiltration into the LUSC TME, define the mechanisms by which this promotes LUSC progression, and to develop novel therapeutic strategies to interrupt these processes.