1303P - Immune-modulating effects on tumor draining lymph nodes following neoadjuvant chemoradiotherapy combined with immunotherapy in patients with T3-4N0-1 NSCLC

Background

The addition of neoadjuvant immunotherapy to chemoradiotherapy (CRT) prior to surgical resection was investigated in locally advanced non-small cell lung cancer (NSCLC) patients (INCREASE trial, NTR-NL8435). Tumor-draining lymph nodes (TDLN) play a key role in the immune response against tumors and are often part of the healthy surrounding tissue exposed to radiotherapy. This study investigated the immune-modulating effects of neoadjuvant immunotherapy and CRT on TDLN in T3-4N0-1 NSCLC patients.

Methods

Resected TDLN were collected from: (i) participants in the INCREASE trial who received neoadjuvant ipilimumab/nivolumab combined with CRT (n=25), and (ii) a control cohort of matched NSCLC patients treated with standard CRT induction therapy (n=25). TDLN were selected based on radiation dose received [low (<5 Gy), intermediate (20-30 Gy) or high dose (50-60 Gy)] and stained with duplex immunohistochemistry for CD8/Ki67, PD1/FOXP3 and CD8/cleaved caspase-3. Hotspot areas were then manually analyzed.

Results

Higher counts of proliferating CD8 T-cells were observed within TDLN in all three categories of radiation exposure in the INCREASE cohort compared to control patients (p=<0.0001, p=0.02, p=<0.0001 for low, intermediate and high dose), as well as higher counts of activated PD-1+ Tregs (p=<0.0001 for all nodes). Furthermore, higher numbers of Ki67+ CD8 T-cells and PD-1+ Tregs were observed with increasing radiation dose (INCREASE high-dose vs low-dose, p=0.0095 for CD8 T-cells and p=0.0298 for Tregs). No relationship was observed between radiation dose exposure and the induction of apoptosis by cleaved caspase-3 in CD8 T-cells.

Conclusions

Higher rates of proliferating CD8 T cells and activated PD-1+ Tregs in TDLN were seen when immunotherapy was added to induction CRT in T3-4N0-1 NSCLC patients, suggesting the enhanced priming of effector CD8 T-cells, accompanied by a simultaneous increase in Tregs. High radiation dose led to an increase of CD8 T-cells and Tregs in the INCREASE cohort. Further analyses with spatial transcriptomics and quantitative pathology imaging is needed to reveal spatial positioning of PD-1+ Tregs in relation to proliferating CD8 T-cells.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

C. Dickhoff: Financial Interests, Advisory Board: AstraZeneca, Bristol Myers Squibb; Financial Interests, Research Grant: AstraZeneca, Bristol Myers Squibb. I. Bahce: Financial Interests, Institutional, Advisory Board: BMS, Boehringer Ingelheim, AstraZeneca, Roche, Pfizer, Takeda, MSD; Financial Interests, Institutional, Research Grant: BMS, Boehringer Ingelheim, AstraZeneca. S. Senan: Financial Interests, Personal, Advisory Board, Ad boards on SCLC and NSCLC: AstraZeneca; Financial Interests, Personal, Advisory Board, Panel to assess treatment toxicity: MSD; Financial Interests, Personal, Advisory Board, NSCLC presentation: Jansen; Financial Interests, Personal, Advisory Board, Adjudication of lung toxicity in non-metastatic lung cancer: MSD; Financial Interests, Personal, Advisory Board, Advisory board: Roche; Financial Interests, Institutional, Research Grant, Funded PhD studentship to study patterns of care in early-stage lung cancer: AstraZeneca; Financial Interests, Institutional, Funding, Funded trials evaluating in preoperative chemo-immune-radiotherapy and in radio-immunotherapy in stage IV NSCLC: BMS; Financial Interests, Institutional, Funding, Co-PI of an institutional trial evaluating a palliative radiotherapy workflow: Varian Medical Systems; Financial Interests, Institutional, Funding, Co-PI of an institutional trial evaluating immune effects of ablative radiotherapy of adrenal metastases: ViewRay Inc; Non-Financial Interests, Leadership Role, Co-investigator for a phase III trial evaluating adjuvant immunotherapy in SCLC: AstraZeneca. F. Schneiders: Financial Interests, Research Grant: Viewray; Financial Interests, Other, Honoraria or consultation fees: AstraZeneca. All other authors have declared no conflicts of interest.