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The non-small cell lung cancer immune landscape: emerging complexity, prognostic relevance and prospective significance in the context of immunotherapy

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Immunotherapy of non-small cell lung cancer (NSCLC), by immune checkpoint inhibitors, has profoundly improved the clinical management of advanced disease. However, only a fraction of patients respond and no effective predictive factors have been defined. Here, we discuss the prospects for identification of such predictors of response to immunotherapy, by fostering an in-depth analysis of the immune landscape of NSCLC. The emerging picture, from several recent studies, is that the immune contexture of NSCLC lesions is a complex and heterogeneous feature, as documented by analysis for frequency, phenotype and spatial distribution of innate and adaptive immune cells, and by characterization of functional status of inhibitory receptor+ T cells. The complexity of the immune landscape of NSCLC stems from the interaction of several factors, including tumor histology, molecular subtype, main oncogenic drivers, nonsynonymous mutational load, tumor aneuploidy, clonal heterogeneity and tumor evolution, as well as the process of epithelial–mesenchymal transition. All these factors contribute to shape NSCLC immune profiles that have clear prognostic significance. An integrated analysis of the immune and molecular profile of the neoplastic lesions may allow to define the potential predictive role of the immune landscape for response to immunotherapy.

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Abbreviations

ADC:

Adenocarcinoma

DFS:

Disease-free survival

EEC:

Early effector cell

eMDSC:

Early MDSC

EMT:

Epithelial mesenchymal transition

GC:

Germinal center

ICB:

Immune checkpoint blockade

IR:

Inhibitory receptor

MDSC:

Myeloid-derived suppressor cell

M-MDSC:

Monocytic MDSC

nLung:

Non-neoplastic lung tissue

NSCLC:

Non-small cell lung cancer

OS:

Overall survival

PFS:

Progression-free survival

PI:

Proximal inflammatory

PMN-MDSC:

Polymorphonuclear MDSC

PP:

Proximal proliferative

SCC:

Squamous cell carcinoma

SCNA:

Somatic copy number alteration

TCR:

T cell receptor

TEM:

T effector memory

TEMRA:

T effector memory RA

Tex:

Exhausted T cell

TH1:

Type 1 T Helper cell

TH2:

Type 2 T Helper cell

TH17:

T Helper 17 cell

Ti-BALT:

Tumor-induced bronchus-associated lymphoid tissues

TIL:

Tumor-infiltrating lymphocyte

TLS:

Tertiary lymphoid structure

Treg:

Regulatory T cell

TRU:

Terminal respiratory unit

t-SNE:

t-distributed stochastic neighbor embedding

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Acknowledgements

The authors gratefully acknowledge the excellent technical contribution of Mrs. Claudia Vegetti, Alessandra Molla, Ilaria Bersani and Paola Baldassari to the work mentioned in this paper.

Funding

The work mentioned in this paper was supported by Grant #17431 from Associazione Italiana per la Ricerca sul Cancro (A. I. R. C.) to Andrea Anichini. Elena Tassi was supported by a fellowship from Fondazione Beretta-Berlucchi. Giulia Grazia was supported by a fellowship from Fondazione Italiana per la Ricerca sul Cancro (FIRC).

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Authors and Affiliations

  1. Department of Research, Human Tumors Immunobiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy

    Andrea Anichini, Elena Tassi, Giulia Grazia & Roberta Mortarini

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  1. Andrea Anichini
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  2. Elena Tassi
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  3. Giulia Grazia
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  4. Roberta Mortarini
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Contributions

AA designed the structure of the review and took the lead in writing the paper. ET and GG contributed to select and review the mentioned literature and to the final revision of the text. RM contributed to design and writing of the paper and to selecting and reviewing all of the mentioned literature.

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Correspondence to Andrea Anichini.

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The authors declare that they have no conflicts of interest.

Additional information

This paper is a Focussed Research Review based on a presentation given at the Fourteenth Meeting of the Network Italiano per la Bioterapia dei Tumori (NIBIT) on Cancer Bio-Immunotherapy, held in Siena, Italy, 13th–15th October 2016. It is part of a series of Focussed Research Reviews and meeting report in Cancer Immunology, Immunotherapy.

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Anichini, A., Tassi, E., Grazia, G. et al. The non-small cell lung cancer immune landscape: emerging complexity, prognostic relevance and prospective significance in the context of immunotherapy. Cancer Immunol Immunother 67, 1011–1022 (2018). https://doi.org/10.1007/s00262-018-2147-7

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