Tumor Microenvironment Determinants of TKI Response in Oncogene-Driven Lung Cancer

1 Research: Tyrosine kinase inhibitors (TKIs) such as alectinib have transformed survival outcomes for patients 2 newly diagnosed with anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC). For 3 most patients, initial TKI therapy results in tumor response but with variable levels of disease shrinkage and

4 control. Extrinsic factors for this variability, such as the immune system, have not been well studied as these 5 tumors are considered immunologically “cold.” However, our data suggests immune cells within the tumor 6 microenvironment (TME) shape the extent of TKI response. Patients with ALK+ NSCLC experience faster

7 disease progression on TKI with increasing numbers of neutrophils in pre-treatment biopsies. Further, their 8 overall survival is significantly shorter on TKI when cancer cells have increased transcriptional activity of 9 CXCL5 and CXCL8, potent chemoattractants for neutrophils. We believe neutrophils within the ALK+ NSCLC

10 TME impair tumor reactive CD8+ T cells. Murine models of ALK+ NSCLC require CD8+ T cells, but not CD4+ 11 T cells, for a sustained alectinib response and tumor clearance. Analogous to the patients, the ALK+ NSCLC 12 murine model that upregulates potent chemoattractants for neutrophils, contains 1) increased Ly6G+

13 neutrophils and 2) fewer activated CD8+ T cells in the TME, and 3) reduced responsiveness to alectinib. Our 14 central hypothesis is that the recruitment of neutrophils by tumor mediated cytokines decreases alectinib 15 responsiveness by impairing anti-tumor T cells. In this proposal, using orthotopic mouse models of ALK+

16 NSCLC, we will determine how neutrophils modulate the TME and CD8+ T cell responses in ALK+ NSCLC. 17 Candidate: Dr. Erin Schenk's career goal is to become a leading laboratory-based physician scientist 18 identifying critical TME immune cells that drive treatment response in ALK+ NSCLC. She will apply innovative

19 technologies and model systems to generate scientific rationale for clinical trials testing novel immunotherapies 20 in patients with NSCLC. To reach this goal, Dr. Schenk will master CRISPR to modify the immune TME 21 content in mouse models of ALK+ NSCLC, test for TKI response, and apply unbiased approaches to explore

22 the TME with scRNAseq, full spectral flow cytometry, and spatial transcriptomics. In parallel, she will acquire 23 the skill sets necessary for clinical trial development and implementation. 24 Environment: The University of Colorado is the only NCI-designated cancer center in Colorado and has an

25 international reputation in clinical and translational work in ALK+ NSCLC. Dr. Schenk has ready access to 26 multiple shared resources (cores) across the cancer center, on line and in person graduate level didactic 27 courses, institutional support from the Thoracic Oncology Program and the Division of Medical Oncology. She

28 has assembled a panel of accomplished mentors including TME expert Dr. Raphael Nemenoff, tumor 29 immunologists Drs. Eduardo Davila and Jill Slansky, neutrophil expert Dr. Sean Colgan, and international 30 ALK+ NSCLC expert and clinical trialist Dr. Ross Camidge. 31