Distinct pretreatment innate immune landscape and posttreatment T cell responses underlie immunotherapy-induced colitis
Immune-related adverse events represent a major hurdle to the success of immunotherapy. The immunological mechanisms underlying their development and relation to antitumor responses are poorly understood. By examining both systemic and tissue-specific immune changes induced by combination anti–CTLA-...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-11-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.157839 |
| _version_ | 1797634351328919552 |
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| author | Kazi J. Nahar Felix Marsh-Wakefield Robert V. Rawson Tuba N. Gide Angela L. Ferguson Ruth Allen Camelia Quek Ines Pires da Silva Stephen Tattersal Christopher J. Kiely Neomal Sandanayake Matteo S. Carlino Geoff McCaughan James S. Wilmott Richard A. Scolyer Georgina V. Long Alexander M. Menzies Umaimainthan Palendira |
| author_facet | Kazi J. Nahar Felix Marsh-Wakefield Robert V. Rawson Tuba N. Gide Angela L. Ferguson Ruth Allen Camelia Quek Ines Pires da Silva Stephen Tattersal Christopher J. Kiely Neomal Sandanayake Matteo S. Carlino Geoff McCaughan James S. Wilmott Richard A. Scolyer Georgina V. Long Alexander M. Menzies Umaimainthan Palendira |
| author_sort | Kazi J. Nahar |
| collection | DOAJ |
| description | Immune-related adverse events represent a major hurdle to the success of immunotherapy. The immunological mechanisms underlying their development and relation to antitumor responses are poorly understood. By examining both systemic and tissue-specific immune changes induced by combination anti–CTLA-4 and anti–PD-1 immunotherapy, we found distinct repertoire changes in patients who developed moderate-severe colitis, irrespective of their antitumor response to therapy. The proportion of circulating monocytes were significantly increased at baseline in patients who subsequently developed colitis compared with patients who did not develop colitis, and biopsies from patients with colitis showed monocytic infiltration of both endoscopically and histopathologically normal and inflamed regions of colon. The magnitude of systemic expansion of T cells following commencement of immunotherapy was also greater in patients who developed colitis. Importantly, we show expansion of specific T cell subsets within inflamed regions of the colon, including tissue-resident memory CD8+ T cells and Th1 CD4+ T cells in patients who developed colitis. Our data also suggest that CD8+ T cell expansion was locally induced, while Th1 cell expansion was systemic. Together, our data show that exaggerated innate and T cell responses to combination immunotherapy synergize to propel colitis in susceptible patients. |
| first_indexed | 2024-03-11T12:06:27Z |
| format | Article |
| id | doaj.art-3735f33fbccb4897a34d7c5e7b464466 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:06:27Z |
| publishDate | 2022-11-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-3735f33fbccb4897a34d7c5e7b4644662023-11-07T16:24:47ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-11-01721Distinct pretreatment innate immune landscape and posttreatment T cell responses underlie immunotherapy-induced colitisKazi J. NaharFelix Marsh-WakefieldRobert V. RawsonTuba N. GideAngela L. FergusonRuth AllenCamelia QuekInes Pires da SilvaStephen TattersalChristopher J. KielyNeomal SandanayakeMatteo S. CarlinoGeoff McCaughanJames S. WilmottRichard A. ScolyerGeorgina V. LongAlexander M. MenziesUmaimainthan PalendiraImmune-related adverse events represent a major hurdle to the success of immunotherapy. The immunological mechanisms underlying their development and relation to antitumor responses are poorly understood. By examining both systemic and tissue-specific immune changes induced by combination anti–CTLA-4 and anti–PD-1 immunotherapy, we found distinct repertoire changes in patients who developed moderate-severe colitis, irrespective of their antitumor response to therapy. The proportion of circulating monocytes were significantly increased at baseline in patients who subsequently developed colitis compared with patients who did not develop colitis, and biopsies from patients with colitis showed monocytic infiltration of both endoscopically and histopathologically normal and inflamed regions of colon. The magnitude of systemic expansion of T cells following commencement of immunotherapy was also greater in patients who developed colitis. Importantly, we show expansion of specific T cell subsets within inflamed regions of the colon, including tissue-resident memory CD8+ T cells and Th1 CD4+ T cells in patients who developed colitis. Our data also suggest that CD8+ T cell expansion was locally induced, while Th1 cell expansion was systemic. Together, our data show that exaggerated innate and T cell responses to combination immunotherapy synergize to propel colitis in susceptible patients.https://doi.org/10.1172/jci.insight.157839ImmunologyOncology |
| spellingShingle | Kazi J. Nahar Felix Marsh-Wakefield Robert V. Rawson Tuba N. Gide Angela L. Ferguson Ruth Allen Camelia Quek Ines Pires da Silva Stephen Tattersal Christopher J. Kiely Neomal Sandanayake Matteo S. Carlino Geoff McCaughan James S. Wilmott Richard A. Scolyer Georgina V. Long Alexander M. Menzies Umaimainthan Palendira Distinct pretreatment innate immune landscape and posttreatment T cell responses underlie immunotherapy-induced colitis JCI Insight Immunology Oncology |
| title | Distinct pretreatment innate immune landscape and posttreatment T cell responses underlie immunotherapy-induced colitis |
| title_full | Distinct pretreatment innate immune landscape and posttreatment T cell responses underlie immunotherapy-induced colitis |
| title_fullStr | Distinct pretreatment innate immune landscape and posttreatment T cell responses underlie immunotherapy-induced colitis |
| title_full_unstemmed | Distinct pretreatment innate immune landscape and posttreatment T cell responses underlie immunotherapy-induced colitis |
| title_short | Distinct pretreatment innate immune landscape and posttreatment T cell responses underlie immunotherapy-induced colitis |
| title_sort | distinct pretreatment innate immune landscape and posttreatment t cell responses underlie immunotherapy induced colitis |
| topic | Immunology Oncology |
| url | https://doi.org/10.1172/jci.insight.157839 |
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