Abstract 188P
Background
The composition and functional state of the tumor immune-environment (TIME) is a critical factor for response to immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC). In the neoadjuvant setting, the composition of the TIME and the spatial distribution of immune effector cells are captured in the pre-operative biopsy (IB). It remains unknown how (a) TIME changes during neoadjuvant ICI treatment and (b) how immune phenotyping of the IB is predictive for response to ICI therapy.
Methods
We performed digital pathology analysis of tumor tissue obtained from patients with stage IIIA(N2) NSCLC undergoing sequential neoadjuvant chemo-immunotherapy including durvalumab in the phase II trial SAKK 16/14. 14 cases with matched IB and resection specimens were included and analyzed by immunostaining for CD3, CD8 and CD20. Two pathologists consensus-reviewed all cases and assigned global immune phenotypes for each case as excluded (“cold tumors”) or inflamed (“hot tumors”). A machine-learning classifier was trained to segment invasive tumor regions and quantify immune cell infiltrates in epithelial and stromal compartments. CD20 stains were used for digital morphometry of tertiary lymphoid structure (TLS) in TIME. Correlations of TIME parameters with event-free survival (EFS) were analyzed by Mann-Whitney-Wilcox test.
Results
Analysis of CD8+ T-cell density in the IB (n = 14) classified TIME as excluded (n = 10) or inflamed (n = 4). Presence of TLS in IB and TLS size strongly correlated with long term EFS (p < 0.001). In cases with mature TLS in the IB, a trend towards increased CD8+ T-cell density and increased infiltration into the tumor epithelial compartment was observed. In analysis of matched IB and resections at individual patient level, an activated TIME was found after neoadjuvant anti-PD-L1 treatment. Specifically, we observed a trend towards increased T-cell density and increasing TLS size in the matched resection specimen after ICI, with the highest fold increase found in patients with long term EFS.
Conclusions
In the trial SAKK16/14, presence of TLS and TLS size in the IB correlate with EFS and a signature of immune activation in the matched resection specimen.
Legal entity responsible for the study
Swiss Group for Clinical Cancer Research (SAKK).
Funding
AstraZeneca, RisingTide Foundation, Gateway for Cancer Research.
Disclosure
S.I. Rothschild: Financial Interests, Institutional, Research Grant: AstraZeneca, AbbVie, Amgen, BMS, Boehringer Ingelheim, Foundation Medicine, Merck, Roche Pharma; Financial Interests, Institutional, Advisory Board: AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eisai, Eli Lilly, Janssen, Merck Serono, MSD, Novartis, Otsuka, PharmaMar, Roche Pharma, Sanofi Aventis, Takeda, BMS; Financial Interests, Institutional, Invited Speaker: Amgen, AstraZeneca, BMS, Janssen, MSD, Novartis, Roche Pharma, Roche Diagnostics, Sanofi, Takeda; Non-Financial Interests, Personal, Member of the Board of Directors: Swiss Group for Clinical Cancer Research; Non-Financial Interests, Personal, Member: Federal Drug Commission, Federal Office of Public Health Switzerland. All other authors have declared no conflicts of interest.