Developing a definition of immune exclusion in cancer: results of a modified Delphi workshop

Abstract

Checkpoint inhibitors represent an effective treatment approach for a variety of cancers through their inhibition of immune regulatory pathways within the tumor microenvironment (TME). Unfortunately only a minority of patients with cancer achieve clinical benefit from immunotherapy, with the TME emerging as an important predictor of outcomes and sensitivity to therapy. The extent and pattern of T-cell infiltration can vary prominently within/across tumors and represents a biological continuum. Three immune profiles have been identified along this continuum: ‘immune-desert’ or ‘T-cell cold’ phenotype, ‘immune-active’, ‘inflamed’, or ‘T-cell hot’ phenotype, and ‘immune excluded’ phenotype. Of the three profiles, immune excluded remains the most ill-defined with no clear, universally accepted definition even though it is commonly associated with lack of response to immune checkpoint inhibitors and poor clinical outcomes. To address this, 16 multidisciplinary cancer experts from around the world were invited to participate in a symposium using a three-round modified Delphi approach. The first round was an open-ended questionnaire distributed via email and the second was an in-person discussion of the first round results that allowed for statements to be revised as necessary to achieve a maximum consensus (75% agreement) among the rating committee (RC). The final round questionnaire was distributed to the RC via email and had a 100% completion rate. The Delphi process resulted in moving us closer to a consensus definition for immune exclusion that is practical, clinically pertinent, and applicable across a wide range of cancer histologies. A general consensus of the role of immune exclusion in resistance to checkpoint therapy and five research priorities emerged from this process. Together, these tools could help efforts designed to address the underlying mechanisms of immune exclusion that span cancer types and, ultimately, aid in the development of treatments to target these mechanisms to improve patient outcomes.

Lectin-like Transcript-1 (LLT1) Expression in Oral Squamous Cell Carcinomas: Prognostic Significance and Relationship with the Tumor Immune Microenvironment

“…After years of research, the complex/heterocellular TIME has emerged as a marker of sensitivity to immunotherapy and a predictor of outcome [20]. Based on TIME composition, tumors have been classified into three different immune profiles [20]: "T cell cold" tumors or "immune desert", showing no lymphocyte infiltration in either tumor nests or within the TIME as a whole; "immune-excluded" tumors, characterized by an intense infiltrate of immune cells in the stroma surrounding tumors nests, but without lymphocyte infiltration into the tumor nests themselves; and finally, "T cell hot", "inflamed" or "immune-active" tumors, defined by the lymphocytic infiltration of tumor nests, with the immune cells in close proximity to tumor cells [21,22]. Kather et al [23] performed an analysis of lymphoid and myeloid phenotypes of human solid tumors and found that immune-excluded tumors were common in head and neck cancers.…”

Targeting T regulatory (Treg) cells in immunotherapy-resistant cancers

“…One important contributor to such resistance is the immunosuppressive tumor microenvironment [ 3 - 5 ] . Based on the state and quality of immune cells, the tumor microenvironment has been classified as immune-inflamed, immune-excluded, and immune-deserted [ 6 , 7 ] . A second classification incorporates the role of cancer-associated fibrosis to describe the response to ICI [ 8 , 9 ] .…”