Intratumoral Versus Circulating Lymphoid Cells as Predictive Biomarkers in Lung Cancer Patients Treated with Immune Checkpoint Inhibitors: Is the Easiest Path the Best One?

Andrea Sesma,Eva M. Gálvez,Irene Torres-Ramón,Alfonso Yubero,Rodrigo Lastra,Ariel Ramírez,Julián Pardo,Maitane Ocáriz,José Ramón Paño,Luis Martínez-Lostao,Marta Gascón,Mara Cruellas,Dolores Isla

doi:10.3390/cells9061525

Abstract

The molecular and cell determinants that modulate immune checkpoint (ICI) efficacy in lung cancer are still not well understood. However, there is a necessity to select those patients that will most benefit from these new treatments. Recent studies suggest the presence and/or the relative balance of specific lymphoid cells in the tumor microenvironment (TEM) including the T cell (activated, memory, and regulatory) and NK cell (CD56dim/bright) subsets, and correlate with a better response to ICI. The analyses of these cell subsets in peripheral blood, as a more accessible and homogeneous sample, might facilitate clinical decisions concerning fast prediction of ICI efficacy. Despite recent studies suggesting that lymphoid circulating cells might correlate with ICI efficacy and toxicity, more analyses and investigation are required to confirm if circulating lymphoid cells are a relevant picture of the lung TME and could be instrumental as ICI response biomarkers. This short review is aimed to discuss the recent advances in this fast-growing field.

Highlights

These findings suggest the existence of an immune response independent of T cells, inhibited by PD-1, and rescued by PD-1 blockade, which was recently identified as depends on Natural Killer cells (NK) cells during cancer [41]
The emergence of ICIs has allowed treating some aggressive cancers, still the number of patients benefiting is relatively low, and good predictive biomarkers to stratify patients according to expected responses are required to increase ICI efficacy and develop new drugs and combination
As summarized in this review, lymphoid cells could be a good biomarker of response both in tumor microenvironment (TME) and peripheral blood

Summary

Introduction

Lung cancer is the most frequent tumor in the world, with more than 2 million new cases estimated in 2018 (11.6% of all cancers), and the one that causes the highest mortality (18.4% all cancers), according to the GLOBOCAN 2018 report [1]. Since every T cell clone expresses a unique TCR, the presence of millions of T lymphocytes in an individual leads to a large and highly variable TCR repertoire which ensures the recognition of a plethora of foreign antigens, including tumor mutated antigens This cell-to-cell contact in the immunological synapse promotes the conversion of naïve CD8+ T lymphocytes into specific antigen-activated cytotoxic T lymphocytes (Tc) capable of eliminating tumor cells. There are still difficulties to know the best way to select patients that will greatly benefit from this type of therapy, and the only biomarker with clinical utility for immunotherapy, such the expression of PD-L1, which has been studied in many clinical trials [6,7,8], is not completely accurate and presents several limitations [9,10,11] Responding to this challenge, several studies have been carried out in order to find predictive response biomarkers to anticipate which patients will respond to each type of treatment, avoid unnecessary toxicities, and reduce costs. Our aim from a translational point of view is to review the most important studies evaluating immune cells as predictive biomarkers of response in lung cancer making special emphasis on the advantages and potential limitations of using samples obtained through minimal invasive procedures such as peripheral blood samples

Tumor Microenvironment

T Cell Memory

Natural Killer Cells

Immune Prognostic Groups

Peripheral Blood

Findings associated with clinical response

Concluding Remarks