CD8+ T cell activation in cancer comprises an initial activation phase in lymph nodes followed by effector differentiation within the tumor

Prokhnevska, Nataliya; Cardenas, Maria A; Valanparambil, Rajesh M.; Sobierajska, Ewelina; Barwick, Benjamin G; Jansen, Caroline S.; Moon, Adriana Reyes; Gregorova, Petra; delBalzo, Luke; Greenwald, Rachel; Bilen, Mehmet Asım; Alemozaffar, Mehrdad; Joshi, Shreyas; Cimmino, Cara; Larsen, Christian; Master, Viraj A.; Sanda, Martin G.; Kissick, Haydn

doi:10.1016/j.immuni.2022.12.002

Cited by 154 publications

(106 citation statements)

References 84 publications

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“…Notably, prior data suggests that the niche is important for supporting and maintaining the CD8 + T cell response within non-CNS tumors. 12 Similarly, here we demonstrate a correlation between immune niche density and the frequency of total CD8 + T cell infiltration, again suggesting that these niches have a supportive role in BrM (Figure 1K). 6 Overall, these data indicate the metastasis to the CNS are infiltrated by distinct functional subsets of CD8 + T cells: a TCF1 + stem-like population, and a TCF1effector-like population.…”

Section: Like T Cells Are Found In Brain Metastases and Reside In An ...supporting

confidence: 75%

“…[6][7][8][9][10] Functional experiments indicate these cells maintain proliferative capacity in the tumor and are likely the source of the anti-tumor effector. 7,8,[11][12][13] Our prior work found these cells reside in close proximity to densely clustered MHC-II + antigen presenting cells (APC), which we termed an antigen presenting niche. 7 In recent work, we found these TCF1 + cells were specific for HPV antigens in head and neck tumors, and upon restimulation with their cognate antigen, underwent proliferation and differentiated to the effector state.…”

Section: Introductionmentioning

confidence: 99%

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Immune niches in brain metastases contain TCF1+ stem-like T cells, are associated with disease control and are modulated by preoperative SRS

Buchwald

Jansen

Prabhu

et al. 2023

Preprint

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The CD8+ T-cell response is prognostic for survival outcomes in several tumor types. However, whether this extends to tumors in the brain, an organ with barriers to T cell entry, remains unclear. Here, we analyzed immune infiltration in 67 brain metastasis (BrM) and found high frequencies of PD1+ TCF1+ stem-like CD8+ T-cells and TCF1- effector-like cells. Importantly, the stem-like cells aggregate with antigen presenting cells in immune niches, and niches were prognostic for local disease control. Standard of care for BrM is resection followed by stereotactic radiosurgery (SRS), so to determine SRS’s impact on the BrM immune response, we examined 76 BrM treated with pre-operative SRS (pSRS). pSRS acutely reduced CD8+ T cells at 3 days. However, CD8+ T cells rebounded by day 6, driven by increased frequency of effector-like cells. This suggests that the immune response in BrM can be regenerated rapidly, likely by the local TCF1+ stem-like population.

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Section: Like T Cells Are Found In Brain Metastases and Reside In An ...supporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Immune niches in brain metastases contain TCF1+ stem-like T cells, are associated with disease control and are modulated by preoperative SRS

Buchwald

Jansen

Prabhu

et al. 2023

Preprint

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“…7C). Indeed, recent data has suggested a two-step model for CD8 + T cell activation in cancer, with initial activation in the TdLN and effector differentiation occurring with co-stimulation in the tumor ( 77 ). The two components of our therapy mirror this paradigm, with αCD4 increasing activation in the TdLN and TA99 + α4-1BB-LAIR enhancing effector functions of these newly activated CD8 + T cells directly in the tumor.…”

Section: Discussionmentioning

confidence: 99%

Tregs constrain CD8⁺T cell priming required for curative intratumorally anchored anti-4-1BB immunotherapy

Palmeri

Lax

Peters

et al. 2023

Preprint

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Although co-stimulation of T cells with agonist antibodies targeting 4-1BB (CD137) improves antitumor immune responses in preclinical studies, clinical development has been hampered by on-target, off-tumor toxicity. Here, we report the development of a tumor-anchored ɑ4-1BB agonist (ɑ4-1BB-LAIR), which consists of an ɑ4-1BB antibody fused to the collagen binding protein LAIR. While combination treatment with an antitumor antibody (TA99) displayed only modest efficacy, simultaneous depletion of CD4+ T cells boosted cure rates to over 90% of mice. We elucidated two mechanisms of action for this synergy: ɑCD4 eliminated tumor draining lymph node Tregs, enhancing priming and activation of CD8+ T cells, and TA99 + ɑ4-1BB-LAIR supported the cytotoxic program of these newly primed CD8+ T cells within the tumor microenvironment. Replacement of ɑCD4 with ɑCTLA-4, a clinically approved antibody that enhances T cell priming, produced equivalent cure rates while additionally generating robust immunological memory against secondary tumor rechallenge.

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“…First, stem-like CD8 T cells were found in aggregates 11 and near blood vessels, but away from tumor cells 14,38 . Second, signals from DCs within the tumor microenvironment have been shown sufficient to differentiate stem-like T cells (newly arrived from lymph nodes) into effector T cells 53,54 .…”

Section: Discussionmentioning

confidence: 99%

Spatial analysis of human lung cancer reveals organized immune hubs enriched for stem-like CD8 T cells and associated with immunotherapy response

Chen

Nieman

Spurrell

et al. 2023

Preprint

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The organization of immune cells in human tumors is not well understood. Immunogenic tumors harbor spatially-localized multicellular 'immunity hubs' defined by expression of the T cell-attracting chemokinesCXCL10/11and abundant T cells. Here, we examined immunity hubs in human pre-immunotherapy lung cancer specimens, and found that they were favorably associated with response to PD1-blockade. Immunity hubs were enriched for many interferon-stimulated genes, T cells in multiple differentiation states, andCXCL9/10/11+ macrophages that preferentially interact with CD8 T cells. Critically, we discovered the stem-immunity hub, a subtype of immunity hub that was strongly associated with favorable PD1-blockade outcomes, distinct from mature tertiary lymphoid structures, and enriched for stem-like TCF7+PD1+ CD8 T cells and activatedCCR7+LAMP3+ dendritic cells, as well as chemokines that organize these cells. These results elucidate the spatial organization of the human intratumoral immune response and its relevance to patient immunotherapy outcomes.

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CD8+ T cell activation in cancer comprises an initial activation phase in lymph nodes followed by effector differentiation within the tumor

Cited by 154 publications

References 84 publications

Immune niches in brain metastases contain TCF1+ stem-like T cells, are associated with disease control and are modulated by preoperative SRS

Immune niches in brain metastases contain TCF1+ stem-like T cells, are associated with disease control and are modulated by preoperative SRS

Tregs constrain CD8⁺T cell priming required for curative intratumorally anchored anti-4-1BB immunotherapy

Spatial analysis of human lung cancer reveals organized immune hubs enriched for stem-like CD8 T cells and associated with immunotherapy response

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CD8+ T cell activation in cancer comprises an initial activation phase in lymph nodes followed by effector differentiation within the tumor

Cited by 154 publications

References 84 publications

Immune niches in brain metastases contain TCF1+ stem-like T cells, are associated with disease control and are modulated by preoperative SRS

Immune niches in brain metastases contain TCF1+ stem-like T cells, are associated with disease control and are modulated by preoperative SRS

Tregs constrain CD8+T cell priming required for curative intratumorally anchored anti-4-1BB immunotherapy

Spatial analysis of human lung cancer reveals organized immune hubs enriched for stem-like CD8 T cells and associated with immunotherapy response

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Tregs constrain CD8⁺T cell priming required for curative intratumorally anchored anti-4-1BB immunotherapy