Beyond cytotoxic T cells: reprogrammed regulatory T cells help facilitate response to dual checkpoint blockade
Combination immunotherapies have entered the treatment armamentarium of oncology, but important knowledge gaps remain in our understanding of how these therapeutics work. A recent study by Rolig, Peng, and colleagues has shed new light on how dual blockade of PD1 and LAG3 enhances antitumor immunity...
Saved in:
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-08-01
|
| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.70076 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850033040145776640 |
|---|---|
| author | Tullia C. Bruno Anthony R. Cillo |
| author_facet | Tullia C. Bruno Anthony R. Cillo |
| author_sort | Tullia C. Bruno |
| collection | DOAJ |
| description | Combination immunotherapies have entered the treatment armamentarium of oncology, but important knowledge gaps remain in our understanding of how these therapeutics work. A recent study by Rolig, Peng, and colleagues has shed new light on how dual blockade of PD1 and LAG3 enhances antitumor immunity. The authors first interrogated LAG3 expression on T cells across murine tumor models, classifying the models as LAG3hi or LAG3lo. Next, they found that LAG3hi models were unresponsive to anti‐PD1 alone but responsive to combination therapy with anti‐PD1 + anti‐LAG3. Surprisingly, the response to anti‐PD1 + anti‐LAG3 in LAG3hi models was associated with reprogramming of CD4+ regulatory T cells (Treg) from the canonically immunosuppressive state to an inflammatory state characterized by loss of expression of the transcription factor Foxp3 and upregulation of transcription factor Tbet. Importantly, an analogous reprogrammed Treg state was associated with response to anti‐PD1 + anti‐LAG3 and longer overall survival in patients with metastatic melanoma. This work highlights the importance of cells beyond cytotoxic CD8+ T cells as drivers of response to immunotherapy and sets the stage for subsequent mechanistic and translational studies. |
| format | Article |
| id | doaj-art-5e1f62a034cb4dcfb145f6192561d6ff |
| institution | DOAJ |
| issn | 1574-7891 1878-0261 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj-art-5e1f62a034cb4dcfb145f6192561d6ff2025-08-20T02:58:22ZengWileyMolecular Oncology1574-78911878-02612025-08-011982163216510.1002/1878-0261.70076Beyond cytotoxic T cells: reprogrammed regulatory T cells help facilitate response to dual checkpoint blockadeTullia C. Bruno0Anthony R. Cillo1UPMC Hillman Cancer Center University of Pittsburgh PA USAUPMC Hillman Cancer Center University of Pittsburgh PA USACombination immunotherapies have entered the treatment armamentarium of oncology, but important knowledge gaps remain in our understanding of how these therapeutics work. A recent study by Rolig, Peng, and colleagues has shed new light on how dual blockade of PD1 and LAG3 enhances antitumor immunity. The authors first interrogated LAG3 expression on T cells across murine tumor models, classifying the models as LAG3hi or LAG3lo. Next, they found that LAG3hi models were unresponsive to anti‐PD1 alone but responsive to combination therapy with anti‐PD1 + anti‐LAG3. Surprisingly, the response to anti‐PD1 + anti‐LAG3 in LAG3hi models was associated with reprogramming of CD4+ regulatory T cells (Treg) from the canonically immunosuppressive state to an inflammatory state characterized by loss of expression of the transcription factor Foxp3 and upregulation of transcription factor Tbet. Importantly, an analogous reprogrammed Treg state was associated with response to anti‐PD1 + anti‐LAG3 and longer overall survival in patients with metastatic melanoma. This work highlights the importance of cells beyond cytotoxic CD8+ T cells as drivers of response to immunotherapy and sets the stage for subsequent mechanistic and translational studies.https://doi.org/10.1002/1878-0261.70076cancer immunologyimmuno‐oncologyimmunotherapyregulatory T cellsTreg fragilityTreg stability |
| spellingShingle | Tullia C. Bruno Anthony R. Cillo Beyond cytotoxic T cells: reprogrammed regulatory T cells help facilitate response to dual checkpoint blockade Molecular Oncology cancer immunology immuno‐oncology immunotherapy regulatory T cells Treg fragility Treg stability |
| title | Beyond cytotoxic T cells: reprogrammed regulatory T cells help facilitate response to dual checkpoint blockade |
| title_full | Beyond cytotoxic T cells: reprogrammed regulatory T cells help facilitate response to dual checkpoint blockade |
| title_fullStr | Beyond cytotoxic T cells: reprogrammed regulatory T cells help facilitate response to dual checkpoint blockade |
| title_full_unstemmed | Beyond cytotoxic T cells: reprogrammed regulatory T cells help facilitate response to dual checkpoint blockade |
| title_short | Beyond cytotoxic T cells: reprogrammed regulatory T cells help facilitate response to dual checkpoint blockade |
| title_sort | beyond cytotoxic t cells reprogrammed regulatory t cells help facilitate response to dual checkpoint blockade |
| topic | cancer immunology immuno‐oncology immunotherapy regulatory T cells Treg fragility Treg stability |
| url | https://doi.org/10.1002/1878-0261.70076 |
| work_keys_str_mv | AT tulliacbruno beyondcytotoxictcellsreprogrammedregulatorytcellshelpfacilitateresponsetodualcheckpointblockade AT anthonyrcillo beyondcytotoxictcellsreprogrammedregulatorytcellshelpfacilitateresponsetodualcheckpointblockade |