2323P - Multi-omic spatial phenotyping of the NSCLC tumour microenvironment for the development of a spatial score associated with immunotherapy resistance

Background

Non-small cell lung cancers (NSCLC) are the leading cause of cancer morbitidy and mortality globally with a 5-year survival of ∼15-20%. Immunotherapies have shown durable benefit in a subset of patients. There is a growing need to identify better biomarkers able to stratify patients who are likely to respond to therapy. Whilst PD-L1 expression and other assessments such as tumour mutation burden (TMB), microsatellite instability (MSI) have shown associations with patient outcomes, there remains a need to comprehensively characterize the tumour microenvironment (TME).

Methods

In this study, we used high-dimensional spatial transcriptome and proteomic profiling of whole slides from NSCLC patients who had received single-agent immunotherapy. We performed a combination of compartmentalized (tumour/stroma) 1800-plex RNA (Nanostring Technologies, Cancer Transcriptome Atlas) and whole-slide 57-plex Phenocycler Fusion and custom Phenocode Signature Panels (Akoya Biosciences) targeting immune contexture, immune profiles, activation status, metabolic activity and immune checkpoints.

Results

For our transcriptome analysis, we compared the tumour and stromal compartments associations with response to therapy (RECIST). The tumour compartments showed specific enrichment for metabolic pathways in patients that were non-responsive to immunotherapy. These findings were further strengthened at the protein level with a grouping of metabolic signatures, including Glucose Transporter 1 (GLUT-1), Glucose-6-phosphate dehydrogenase (G6PD) and Citrase Synthase (CS). In resistant tumours, there was a clear lack of CD8 and CD68 infiltration and reduction or absence of lymphoid/tertiary lymphoid-like structures highlighting the complementarity of T- and B-cell biology in areas of high metabolic activity.

Conclusions

This study identifies a unique metabolic signature associated with response and resistance to immunotherapy in NSCLC which is mirrored by T- and B-cell biology. Our study demonstrates the utility of high-dimensional spatial multi-omic profiling to delineate new signatures associated with response to therapy and aid in patient stratification.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

N. Ma, A. Pratapa, O. Braubach: Financial Interests, Institutional, Full or part-time Employment: Akoya Biosciences. K.J. O'Byrne: Financial Interests, Personal, Other, Advisor/consultant on project development by the company: TriStar; Financial Interests, Personal, Other, Invited speaker; advisory board: BMS; Financial Interests, Personal, Other, Advisory board; invited speaker: AstraZeneca, MSD, Janssen; Financial Interests, Personal, Other, advisory board; invited speaker: Roche; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Takeda; Financial Interests, Personal, Other, Advisory board: Pfizer; Financial Interests, Personal, Invited Speaker: Astellas; Financial Interests, Personal, Advisory Board, Advice on development of lasertinib: Yuhan; Financial Interests, Personal, Advisory Board, Advice re cabozantinib: Ipsen; Financial Interests, Personal, Advisory Board, Advice of drug development program: Beigene; Financial Interests, Personal, Invited Speaker, Topic - tepotinib: Merck; Financial Interests, Personal, Other, Sponsorship for travel, accommodation and registration for ESMO Congress, Paris, 2022: Bayer; Financial Interests, Personal, Stocks/Shares, 5% non-dilutable shares in a start-up Pharma company: RepLuca Pharmaceuticals Pty Ltd.; Financial Interests, Personal, Stocks/Shares, Start-up diagnostics focused on genomics: DGC diagnostics; Financial Interests, Personal, Other, Co-founder, Board Member and Share Holder (15%) in the Pharma and biotech company: Carpe Vitae Pharmaceuticals Pty Ltd.; Financial Interests, Personal, Steering Committee Member, Steering Committee Member 2 trials- CA-209-227- CA-224-095: BMS; Financial Interests, Personal, Steering Committee Member, Steering Committee Member LUX-Lung program: Boehringer Ingelheim; Non-Financial Interests, Other, Chair an education session: Foundation Medicine. All other authors have declared no conflicts of interest.