Blockade of LAG-3 and PD-1 leads to co-expression of cytotoxic and exhaustion gene modules in CD8+T cells to promote antitumor immunity

被引：58

作者：

Cillo, Anthony R. ^{[1
,2
,6
]}

Cardello, Carly ^{[1
,2
]}

Shan, Feng ^{[1
,2
,3
]}

Karapetyan, Lilit ^{[4
,7
]}

Kunning, Sheryl ^{[1
,2
]}

Sander, Cindy ^{[4
]}

Rush, Elizabeth ^{[4
]}

Karunamurthy, Arivarasan ^{[5
]}

Massa, Ryan C. ^{[4
,8
]}

Rohatgi, Anjali ^{[4
,9
]}

Workman, Creg J. ^{[1
,2
]}

Kirkwood, John M. ^{[1
,2
,4
,6
]}

Bruno, Tullia C. ^{[1
,2
,6
]}

Vignali, Dario A. A. ^{[1
,2
,6
]}

机构：

[1] Univ Pittsburgh, Sch Med, Dept Immunol, Pittsburgh, PA 15260 USA

[2] Univ Pittsburgh, Tumor Microenvironm Ctr, UPMC Hillman Canc Ctr, Sch Med, Pittsburgh, PA 15260 USA

[3] Univ Pittsburgh, Integrat Syst Biol ISB Grad Program, Sch Med, Pittsburgh, PA USA

[4] Univ Pittsburgh, Sch Med, Dept Med, Div Hematol Oncol, Pittsburgh, PA 15260 USA

[5] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA

[6] UPMC Hillman Canc Ctr, Canc Immunol & Immunotherapy Program, Pittsburgh, PA 15232 USA

[7] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA

[8] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA USA

[9] Washington Univ, Sch Med, Dept Med, Div Oncol, St Louis, MO USA

来源：

CELL | 2024年 / 187卷 / 16期

关键词：

CD8(+) T-CELLS; ANTI-PD-1; THERAPY; SIGNATURES; NIVOLUMAB; INFERENCE; RATIO; CD28;

D O I：

10.1016/j.cell.2024.06.036

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Relatlimab (rela; anti-LAG-3) plus nivolumab (nivo; anti-PD-1) is safe and effective for treatment of advanced melanoma. We designed a trial (NCT03743766) where advanced melanoma patients received rela, nivo, or rela+nivo to interrogate the immunologic mechanisms of rela+nivo. Analysis of biospecimens from this ongoing trial demonstrated that rela+nivo led to enhanced capacity for CD8+ T cell receptor signaling and altered CD8+ T cell differentiation, leading to heightened cytotoxicity despite the retention of an exhaustion profile. Co-expression of cytotoxic and exhaustion signatures was driven by PRDM1, BATF, ETV7, and TOX. Effector function was upregulated in clonally expanded CD8+ T cells that emerged after rela+nivo. A rela+nivo intratumoral CD8+ T cell signature was associated with a favorable prognosis. This intratumoral rela+nivo signature was validated in peripheral blood as an elevated frequency of CD38+TIM3+CD8+ T cells. Overall, we demonstrated that cytotoxicity can be enhanced despite the retention of exhaustion signatures, which will inform future therapeutic strategies.

引用

页码：4373 / 4388.e15

页数：32

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