Multi-omic and spatial dissection of immunotherapy response groups in non-small cell lung cancer

James Monkman; Honesty Kim; Aaron Mayer; Ahmed Mehdi; Nicholas Matigian; Marie Cumberbatch; Milan Bhagat; Rahul Ladwa; Scott N Mueller; Mark N Adams; Ken O'Byrne; Arutha Kulasinghe

doi:10.1111/imm.13646

Multi-omic and spatial dissection of immunotherapy response groups in non-small cell lung cancer

Immunology. 2023 Aug;169(4):487-502. doi: 10.1111/imm.13646. Epub 2023 Apr 6.

Authors

James Monkman¹, Honesty Kim², Aaron Mayer², Ahmed Mehdi³, Nicholas Matigian³, Marie Cumberbatch⁴, Milan Bhagat⁴, Rahul Ladwa⁵, Scott N Mueller⁶, Mark N Adams⁷, Ken O'Byrne^{5

7}, Arutha Kulasinghe¹

Affiliations

¹ Frazer Institute, Faculty of Medicine, The University of Queensland, Woolloongabba, Brisbane, Queensland, 4102, Australia.
² Enable Medicine, Menlo Park, California, USA.
³ QFAB Bioinformatics, The University of Queensland, Brisbane, Queensland, Australia.
⁴ Tristar Technologies Group, Rockville, Maryland, USA.
⁵ Princess Alexandra Hospital, Brisbane, Queensland, Australia.
⁶ Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
⁷ Queensland University of Technology, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Brisbane, Queensland, Australia.

PMID: 37022147
DOI: 10.1111/imm.13646

Abstract

The composition and activation status of the cellular milieu contained within the tumour microenvironment (TME) is becoming increasingly recognized as a driving factor for immunotherapy response. Here, we employed multiplex immunohistochemistry (mIHC), and digital spatial profiling (DSP) to capture the targeted immune proteome and transcriptome of tumour and TME compartments from an immune checkpoint inhibitor (ICI)-treated (n = 41) non-small cell lung cancer (NSCLC) patient cohort. We demonstrate by mIHC that the interaction of CD68⁺ macrophages with PD1⁺ , FoxP3⁺ cells is enriched in ICI refractory tumours (p = 0.012). Patients responsive to ICI therapy expressed higher levels of IL2 receptor alpha (CD25, p = 0.028) within their tumour compartments, which corresponded with increased IL2 mRNA (p = 0.001) within their stroma. In addition, stromal IL2 mRNA levels positively correlated with the expression of pro-apoptotic markers cleaved caspase 9 (p = 2e^-5 ) and BAD (p = 5.5e^-4 ) and negatively with levels of memory marker, CD45RO (p = 7e^-4 ). Immuno-inhibitory markers CTLA-4 (p = 0.021) and IDO-1 (p = 0.023) were suppressed in ICI-responsive patients. Tumour expression of CD44 was depleted in the responsive patients (p = 0.02), while higher stromal expression of one of its ligands, SPP1 (p = 0.008), was observed. Cox survival analysis also indicated tumour CD44 expression was associated with poorer prognosis (hazard ratio [HR] = 1.61, p = 0.01), consistent with its depletion in ICI-responsive patients. Through multi-modal approaches, we have dissected the characteristics of NSCLC immunotherapy treatment groups and provide evidence for the role of several markers including IL2, CD25, CD44 and SPP1 in the efficacy of current generations of ICI therapy.

Keywords: immunotherapy; lung cancer; multi-omic; multiplex; spatial transcriptomics.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Carcinoma, Non-Small-Cell Lung* / drug therapy
Carcinoma, Non-Small-Cell Lung* / genetics
Humans
Immunotherapy / adverse effects
Interleukin-2
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Multiomics
Tumor Microenvironment

Substances

Interleukin-2