Innate immunity as a mechanism of TKI resistance in fusion-driven NSCLC

2021

Career Development Award

This grant was funded in part by The Huff Project

Erin Schenk, MD, PhD

University of Colorado

Boulder

Fusion-driven NSCLC is a group of lung cancers that are driven by specific changes in oncogenes. These lung cancers tend to be addicted to these oncogenes. Such fusion-driven NSCLCs are treated with targeted therapies that block the effect of the oncogenes. However, the cancer inevitably comes back because the tumors become resistant. Traditionally, fusion-driven NSCLCs have not been successfully treated with immunotherapy. Dr. Schenk is testing how these cancers can be treated with immunotherapy through another immune pathway—the innate immunity pathway.

Research Summary

In patients with non-small cell lung cancer, a subset of tumors carry a genetic alteration resulting in the expression of ALK or ROS1 fusions (FD-NSCLC). These tumors frequently respond to and are controlled by tyrosine kinase inhibitor (TKI) therapy for several years. Eventually, these tumors develop TKI resistance and some of the resistance mechanisms are readily identified in the cancer cells. In a similar portion of patients, the reason for TKI resistance development is unknown. Based on our preliminary data, we propose that the tumor microenvironment (TME), specifically the monocytes and macrophages (MoMf) surrounding the cancer cells, contributes to the development of TKI resistance. However, the potential role of the TME as a mediator of TKI resistance has not been well studied in patients with FD-NSCLC. Using cell lines derived from patients, we observed FD-NSCLC cell lines were more resistant to TKI when grown in MoMf conditioned media. This resistance was associated with increased activation of a key cancer cell signaling pathway that drove the decreased sensitivity to TKI. In pre-treatment biopsy specimens, we found that the TME of patients with FD-NSCLC contained variable levels of MoMf. We believe our preliminary data suggests MoMf within the TME influence patient outcome to TKI therapy. We will test our hypothesis in clinically relevant animal models, patient derived FD-NSCLC cell lines, and patient biopsy specimens. Ultimately, we hope to identify novel MoMf-mediated mechanisms of TKI resistance as there is an urgent need to develop new, more effective therapies for these patients.

Technical Abstract

Patients with non-small cell lung cancers bearing ALK or ROS1 fusions (FD-NSCLC) often experience an initial, marked response to tyrosine kinase inhibitors (TKI). The eventual emergence of TKI resistance in FD-NSCLC can be partially attributed to cancer-cell intrinsic mechanisms, but these do not fully explain the diversity in patient outcomes. Currently, FD-NSCLC is viewed as a “cold” tumor with only a molecular target, and the role of the tumor microenvironment (TME) in these cancers has not been well studied. As patients have limited options after progression on TKIs, there is an urgent need to identify novel drivers of resistance to develop new, more effective therapies. Based on our preliminary data, we believe innate immune cells, monocytes and macrophages (MoMf), within the FD-NSCLC TME shape tumor response to TKI therapy. Using patient derived cell lines, we found marked TKI resistance in multiple FD-NSCLC cell lines when cultured in media conditioned by MoMf. MoMf-driven TKI resistance was associated sustained pERK activity in the cancer cell. In pre-treatment specimens from patients with FD-NSCLC, multispectral tissue imaging demonstrated a range in number of MoMf within the TME. Our preliminary data suggest the presence of MoMf with the FD-NSCLC TME may alter response to therapy. We propose investigating the mechanisms of MoMf-mediated TKI resistance and potential therapeutic approaches with clinically relevant syngeneic and xenograft animal models and patient-derived FD-NSCLC cell lines. Further, we will examine biopsy specimens from patients
Immunotherapy is a treatment approach that leverages the body’s own immune system to destroy cancer cells. In non-small cell lung cancer (NSCLC), the most common type of lung cancer, immunotherapy has opened the door to durable treatment that approaches cure; unfortunately, this outcome is rare, and many NSCLCs are initially or eventually become unresponsive. It was originally thought that unresponsive malignancies had adapted to prevent immune cells from locating and interacting with the tumor. Our research suggests this is not the case: the tumor can remain inflamed and responsive, but the immune response can become exhausted. Therapies that reinvigorate the immune response (including tumor infiltrating lymphocyte [TIL] therapies) may be particularly effective in this context. In fact, our preliminary studies suggest TIL therapy can work in up to a third of treatment-resistant NSCLCs. Capitalizing on these new insights, our proposal seeks to 1) determine pre-treatment features of sensitivity and resistance to TIL therapy in NSCLC and 2) characterize on-treatment patterns of immune response, focusing on the cells that identify and kill NSCLC cells. Accomplishing these aims will fill critical knowledge gaps, identifying characteristics of tumors likely to respond, or that fail to respond, to TIL treatment. These studies will define a roadmap, guiding application of subsequent TIL research for lung cancer. Taken together, these studies will provide crucial insights into novel treatment approaches for patients with few alternatives and an otherwise grim prognosis.

Key words

Acquired resistance

Adenocarcinoma

Immune checkpoint inhibitors

Immunotherapy

Non-small cell lung cancer (NSCLC)

Innate immunity as a mechanism of TKI resistance in fusion-driven NSCLC

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