CD8+ Lymphocyte Infiltration is a Specific Feature of Colitis Induced By Immune Checkpoint Inhibitors

Abstract Background Immune checkpoint inhibitors (ICPIs) have revolutionized cancer therapy, although immune-related adverse events (irAEs) remain a severe issue. The clinical characteristics of colitis induced by ICPIs are very similar to inflammatory bowel disease. Recently, CD8+ lymphocyte infiltration into organs has been associated with the onset of irAEs. The present study compared the histological infiltration of CD8+ lymphocytes in irAE colitis with that in other colitis. Methods Among 102 newly diagnosed and untreated patients, 12 with irAE colitis, 37 with ulcerative colitis (UC), 22 with Crohn's disease (CD), and 31 with ischemic colitis (IC) were retrospectively enrolled. Biopsy specimens were obtained from endoscopic areas of high inflammation for immunohistochemical analysis of the number of CD4+ and CD8+ lymphocytes in the most inflamed high-powered microscopic field. Results In irAE colitis, CD8+ lymphocyte infiltration was significantly greater than that of CD4+ lymphocytes (p < 0.01). The amount of CD8+ lymphocyte infiltration was significantly higher in irAE colitis than in UC (p < 0.05), CD (p < 0.05), and IC (p < 0.01). The CD8+/CD4+ ratio was also significantly higher in irAE colitis (p < 0.01 vs. UC, CD, and IC, respectively). The optimal cut-off CD8+/CD4+ ratio for diagnosing irAE colitis was 1.17 (sensitivity: 83%, specificity: 84%). The optimal cut-off the number of CD8+ lymphocytes for diagnosing irAE colitis was 102 cells/high-power field (sensitivity: 75%, specificity: 81%). Conclusions Greater CD8+ lymphocyte infiltration and a higher CD8+/CD4+ ratio may be simple and useful biomarkers to distinguish irAE colitis from other forms of colitis.

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T-Lymphocyte Infiltration to Islets in the Pancreas of a Patient Who Developed Type 1 Diabetes After Administration of Immune Checkpoint Inhibitors

Diabetes Care ◽

10.2337/dc18-2518 ◽

2019 ◽

Vol 42 (7) ◽

pp. e116-e118 ◽

Cited By ~ 13

Author(s):

Sho Yoneda ◽

Akihisa Imagawa ◽

Yoshiya Hosokawa ◽

Megu Yamaguchi Baden ◽

Takekazu Kimura ◽

...

Keyword(s):

Type 1 Diabetes ◽

T Lymphocyte ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Lymphocyte Infiltration

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Safety of Immune Checkpoint Inhibitors in Patients With Pre-Existing Inflammatory Bowel Disease and Microscopic Colitis

JCO Oncology Practice ◽

10.1200/jop.19.00672 ◽

2020 ◽

Vol 16 (9) ◽

pp. e933-e942 ◽

Cited By ~ 2

Author(s):

Shilpa Grover ◽

Alex B. Ruan ◽

Padmavathi Srivoleti ◽

Anita Giobbie-Hurder ◽

Marta Braschi-Amirfarzan ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Outcome Data ◽

Microscopic Colitis ◽

Patients With Cancer ◽

Inflammatory Bowel

PURPOSE: Enterocolitis is among the leading adverse events associated with immune checkpoint inhibitors (ICIs). There are limited retrospective data regarding the safety of ICIs in patients with inflammatory bowel disease (IBD; ulcerative colitis, Crohn’s disease) because they have been generally excluded from clinical trials testing ICIs. Furthermore, there are no outcome data available in patients with microscopic colitis, a leading cause of chronic diarrhea. We aimed to study the safety of ICIs in patients with cancer with pre-existing IBD or microscopic colitis. METHODS: We retrospectively reviewed the records of patients with cancer treated at our institution who received at least 1 dose of either a programmed cell death-1 (PD-1)/ PD-1 ligand inhibitor, cytotoxic T-lymphocyte-associated antigen 4 inhibitor, or both between 2011 and 2018. We identified patients with pre-existing IBD or microscopic colitis. RESULTS: Of 548 patients with solid tumor treated with an ICI, we identified 25 with pre-existing colitis (21 IBD; 4 microscopic colitis). An enterocolitis flare occurred in 7 patients (28%): 3 of 4 patients (75%) with microscopic colitis and 4 of 21 (19%) with IBD. All were treated with systemic corticosteroids, 2 required an anti–tumor necrosis factor agent, and one required an anti-integrin agent and colectomy for treatment of refractory colitis. ICI therapy was discontinued in all patients who experienced an enterocolitis flare. CONCLUSION: In our cohort, exacerbation of enterocolitis occurred in a notable percentage of patients with IBD and a majority of patients with microscopic colitis, leading to discontinuation of ICIs. Although these data suggest that patients with cancer with pre-existing IBD/microscopic colitis may be treated with ICIs, additional studies are needed to validate our results.

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Primary CNS lymphoma commonly expresses immune response biomarkers

Neuro-Oncology Advances ◽

10.1093/noajnl/vdaa018 ◽

2020 ◽

Vol 2 (1) ◽

Author(s):

Alexander Ou ◽

Ashley Sumrall ◽

Surasak Phuphanich ◽

David Spetzler ◽

Zoran Gatalica ◽

...

Keyword(s):

Rna Sequencing ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Primary Cns Lymphoma ◽

Central Nervous System Lymphoma ◽

Cns Lymphoma ◽

Missense Mutations ◽

High Power Field ◽

Tumor Mutational Burden

Abstract Background Primary central nervous system lymphoma (PCNSL) is rare and there is limited genomic and immunological information available. Incidental clinical and radiographic responses have been reported in PCNSL patients treated with immune checkpoint inhibitors. Materials and Methods To genetically characterize and ascertain if the majority of PCNSL patients may potentially benefit from immune checkpoint inhibitors, we profiled 48 subjects with PCNSL from 2013 to 2018 with (1) next-generation sequencing to detect mutations, gene amplifications, and microsatellite instability (MSI); (2) RNA sequencing to detect gene fusions; and (3) immunohistochemistry to ascertain PD-1 and PD-L1 expression. Tumor mutational burden (TMB) was calculated using somatic nonsynonymous missense mutations. Results High PD-L1 expression (>5% staining) was seen in 18 patients (37.5%), and intermediate expression (1–5% staining) was noted in 14 patients (29.2%). Sixteen patients (33.3%) lacked PD-L1 expression. PD-1 expression (>1 cell/high-power field) was seen in 12/14 tumors (85.7%), uncorrelated with PD-L1 expression. TMB of greater than or equal to 5 mutations per megabase (mt/Mb) occurred in 41/42 tumors, with 19% (n = 8) exhibiting high TMB (≥17 mt/Mb), 71.4% (n = 30) exhibiting intermediate TMB (7–16 mt/Mb), and 9.5% (n = 4) exhibiting low TMB (≤6 mt/Mb). No samples had MSI. Twenty-six genes showed mutations, most frequently in MYD88 (34/42, 81%), CD79B (23/42, 55%), and PIM1 (23/42, 55%). Among 7 cases tested with RNA sequencing, an ETV6-IGH fusion was found. Overall, 18/48 samples expressed high PD-L1 and 38/42 samples expressed intermediate to high TMB. Conclusions Based on TMB biomarker expression, over 90% of PCNSL patients may benefit from the use of immune checkpoint inhibitors.

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