Assessing Tumor-infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method From the International Immunooncology Biomarkers Working Group: Part 1: Assessing the Host Immune Response, TILs in Invasive Breast Carcinoma and Ductal Carcinoma In Situ, Metastatic Tumor Deposits and Areas for Further Research

Abstract

Assessment of tumor-infiltrating lymphocytes (TILs) in histopathologic specimens can provide important prognostic information in diverse solid tumor types, and may also be of value in predicting response to treatments. However, implementation as a routine clinical biomarker has not yet been achieved. As successful use of immune checkpoint inhibitors and other forms of immunotherapy become a clinical reality, the need for widely applicable, accessible, and reliable immunooncology biomarkers is clear. In part 1 of this review we briefly discuss the host immune response to tumors and different approaches to TIL assessment. We propose a standardized methodology to assess TILs in solid tumors on hematoxylin and eosin sections, in both primary and metastatic settings, based on the International Immuno-Oncology Biomarker Working Group guidelines for TIL assessment in invasive breast carcinoma. A review of the literature regarding the value of TIL assessment in different solid tumor types follows in part 2. The method we propose is reproducible, affordable, easily applied, and has demonstrated prognostic and predictive significance in invasive breast carcinoma. This standardized methodology may be used as a reference against which other methods are compared, and should be evaluated for clinical validity and utility. Standardization of TIL assessment will help to improve consistency and reproducibility in this field, enrich both the quality and quantity of comparable evidence, and help to thoroughly evaluate the utility of TILs assessment in this era of immunotherapy.

Figure 1

The cellular constituents of the host immune response to tumors can control tumor growth or contribute to an immunosuppressive environment that promotes tumor progression. Breg, regulatory B cell; DC, dendritic cell; GC B cell, germinal center B cell; IFNγ, interferon gamma; Ig’s, immunoglobulins; IL4, interleukin 4; IL10, interleukin 10; IL17, interleukin 17; IL21, interleukin 21; M, macrophage; MDSC, myeloid derived suppressor cell; N, neutrophil; NK, natural killer cell; NKT, natural killer T cell; Tfh, follicular B helper T cells; Th, helper CD4⁺ T cell; TGFβ, transforming growth factor beta; TILs, tumor-infiltrating lymphocytes; Treg, regulatory T cell.

Figure 2

Guidelines for a standardized approach to TILs evaluation in solid tumors. Modified from Salgado et al [14] with permission from Oxford University Press on behalf of the European Society for Medical Oncology.

Figure 3

The “invasive margin” (IM) is defined as the region centered on the border separating the host tissue from the malignant nests, with an extent of 1mm. “Central tumor” (CT) corresponds to all the tissue inside the IM, and “peri-tumor” (PT) to tissue outside of the IM.

Figure 4

Assessing TILs in metastatic tumor deposits in lymph nodes. Cases showing a desmoplastic stroma can be scored as for the primary lesion, i.e. sTILs may be scored within this reactive stroma (Panels A-D). Panels A and B show an example of a metastatic tumor deposit with clearly distinguishable border between pre-existing lymphoid tissue and tumoral sTILs. Panels C and D show an example with very few sTILs in the stroma of the tumor deposit. In cases without a desmoplastic stroma, TILs are scored only within tumor nests (Panels E and F), i.e. iTILs only. The pre-existing lymphoid stroma is excluded from the evaluation.