Heterogeneous tumor‐immune microenvironments between primary and metastatic carcinoid tumors differentially respond to anti‐PD‐L1 antibody therapy

Abstract

A pulmonary carcinoid tumor is a rare tumor that lacks a validated therapeutic approach for unresectable disease. Understanding the intersite tumor‐immune heterogeneity is essential to harness the immune system for cancer therapy. However, little is known about the tumor‐immune microenvironment (TIME). Here, we describe a patient who had heterogeneous TIME between primary and metastatic carcinoid tumors which differentially responded to chemoimmunotherapy. A 72‐year‐old man was diagnosed with an advanced pulmonary carcinoid tumor. CT‐guided biopsies of lung and scapular tumors confirmed typical carcinoid (PD‐L1, 1%–24%) and atypical carcinoid tumors (PD‐L1, negative), respectively. Although the primary lung carcinoid tumor showed a partial response, the scapular tumor was significantly enlarged after two cycles of anti‐PD‐L1 antibody therapy in combination with carboplatin plus etoposide. We performed quantitative pathology imaging analysis with fluorescent multiplex immunohistochemistry. CD8+ T cell infiltration was detected in the PD‐L1‐positive primary lung tumor nest; however, it was mostly restrained in the stroma in a PD‐L1‐negative metastatic scapular tumor. Treg infiltrations into both tumor nests and stroma were detected in the lung tumor, which were not detected in the metastatic scapular tumor. This study provides the first evidence of coexistence of heterogeneous TIME within a single individual with a pulmonary carcinoid tumor. This study may provide new insights into the mechanism of primary resistance to chemoimmunotherapy in pulmonary carcinoid tumors.

Immune Checkpoint Blockade in Lung Carcinoids with Aggressive Behaviour: One More Arrow in Our Quiver?

“…Heterogeneous immune marker expression in primary and metastatic lesions may be another reason for variable therapeutic responses [44,45]. Of note, discordance of PD-L1 status between the primary lung tumour and metastatic bone deposits was associated with disease progression at follow-up in the above-mentioned case report by Sakata et al [33]. When feasible, analysis of both the primary tumour mass and its secondary foci could therefore enable a better prediction of favourable outcomes with ICIs for an individual patient.…”

“…Sakata et al reported the case of a 72-year-old man with advanced LC and multiple bone metastases receiving atezolizumab in combination with carboplatin plus etoposide as first-line therapy [33]. CT-guided biopsies of the primary lung tumour and a scapular metastasis resulted in the diagnosis of PD-L1-positive, microsatellite stable TC and PD-L1-negative, and microsatellite stable AC, respectively.…”

“…The trial is designed to evaluate the objective response rate, assessed by RECIST 1.1, as the primary endpoint. Several other efficacy and safety outcomes are evaluated as the secondary endpoints, including the objective response, assessed by immune-modified RECIST [33], DOR, PFS, OS, and AEs. The study is also aimed at identifying predictive and prognostic factors, biomarkers associated with resistance to therapy, and biomarkers associated with susceptibility to developing AEs.…”

Clinical Implications and Molecular Characterization of Drebrin-Positive, Tumor-Infiltrating Exhausted T Cells in Lung Cancer

“…The tumor immune microenvironment (TIME) evolves during tumor growth and dissemination [5][6][7]. TIME differs not only between cancer types [8] but also between patients with the same disease [9].…”

“…TILs have been studied as prognostic and/or predictive immune biomarkers for NSCLC [14]. The immune context is defined by the density and location of the TILs [6,7]. The quantification of the spatial patterns of TILs in tumor regions have a significant prognostic value [15][16][17].…”