Therapeutic Implications of the Immunoscore in Patients with Colorectal Cancer.

Carine El Sissy,Franck Pagès,Nacilla Haicheur,Florence Marliot,Guy Zeitoun,Jérôme Galon,Christine Lagorce-Pagès,Amos Kirilovsky

doi:10.3390/cancers13061281

Abstract

Simple SummaryBeyond the TNM-staging system, biomarkers are needed to guide cancer treatments. We provide an overview of the Immunoscore, a standardized immune assay based on quantification by digital pathology of CD3+ and CD8+ cytotoxic T cells in tumor tissues. We discuss the usefulness of the Immunoscore (IS) and biopsies-adapted IS (ISB) biomarkers for prediction of clinical outcome and treatment response in colonic and rectal cancers.Four decades were needed to progress from the first demonstration of the independent prognostic value of lymphocytes infiltration in rectal cancers to the first recommendation from the international guidelines for the use of a standardized immune assay, namely the “Immunoscore” (IS), to accurately prognosticate colon cancers beyond the TNM-system. The standardization process included not only the IS conceptualization, development, fine-tuning, and validation by a large international consortium, but also a demonstration of the robustness and reproducibility across the world and testing of international norms and their effects on the IS. This is the first step of a major change of paradigm that now perceives cancer as the result of contradicting driving forces, i.e., the tumor expansion and the immune response, interacting dynamically and influencing the prognosis and the response to therapies. This prompted us to evaluate and evidence the capacity of the tumor immune status, as reflected by the IS, to accurately predict chemotherapy responses in an international, randomized cohort study of colon cancer. Moreover, we developed a derived IS performed on initial diagnostic biopsies (ISB) to assess response levels to neoadjuvant therapies. In rectal cancer, ISB was positively correlated with the degree of histologic response to neoadjuvant chemoradiotherapy and identified - alone and even more accurately if combined with clinical data- patients eligible for a noninvasive strategy. Based on these results, we are currently setting up an international cohort for confirmation. The potential role of IS with immunotherapies must be anticipated.

Highlights

Colorectal cancer (CRC) stands third most in men and second in women with respect to incidence, accounting for 10% of all cancers worldwide
Biomarkers are needed to guide the standard of care, such as adjuvant chemotherapy in stage III colon cancer or neoadjuvant chemoradiotherapy in locally advanced rectal cancer (LARC), to better select patients who could benefit from treatment beyond the TNM staging and to predict tumor response to new treatments such as immunotherapies
We investigated the ability of the IS to predict response to adjuvant chemotherapy in the Immunoscore-International Duration Evaluation of Adjuvant Chemotherapy (IDEA) France phase III trial (n = 1062 patients, conducted in collaboration with PRODIGE, a digestive oncology French intergroup (GERCOR, FFCD, UNICANCER)) [15], which aimed to evaluate the noninferiority of three versus six months of adjuvant therapy with either FOLFOX or CAPOX in patients with resected stage III CC [16]

Summary

Introduction

Colorectal cancer (CRC) stands third most in men and second in women with respect to incidence, accounting for 10% of all cancers worldwide. Biomarkers are needed to guide the standard of care, such as adjuvant chemotherapy in stage III colon cancer or neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC), to better select patients who could benefit from treatment beyond the TNM staging and to predict tumor response to new treatments such as immunotherapies. Due to moderate prediction accuracy and reproducibility, these did not translate into the clinical practice, except for the molecular phenotype referred to as MSI (microsatellite instability). All these methods, though, mask intratumor heterogeneity and omit both the tumor microenvironment (TME) and components of the immune system. We will discuss the usefulness of the recently validated consensus Immunoscore (IS) and biopsies-adapted IS (ISB) biomarkers for the prediction of clinical outcome and treatment response in the clinical setting

Conceptual Bases and Development of the IS

Immunoscore and Immunotherapy

Findings

Conclusions