Immune evasion of dormant disseminated tumor cells is due to their scarcity and can be overcome by T cell immunotherapies

Goddard, Erica T.; Linde, Miles H.; Srivastava, Shivani; Klug, Grant; Shabaneh, Tamer B.; Iannone, Santino; Grzelak, Candice A.; Marsh, Sydney; Riggio, Alessandra I.; Shor, Ryann E.; Linde, Ian L.; Guerrero, Marissa; Veatch, Joshua R.; Snyder, Annelise G.; Welm, Alana L.; Riddell, Stanley R.; Ghajar, Cyrus M.

doi:10.1016/j.ccell.2023.12.011

Cited by 8 publications

(3 citation statements)

References 78 publications

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“…The mechanisms by which dormant tumor cells preclude the recruitment or function of activated T cells remain largely unknown, but a leading hypothesis is that dormant cells persist likely due to poor interaction with endogenous antigen-specific T cells, a relatively rare population [ 91 , 92 ]. However, in a model of triple-negative breast cancer (TNBC), despite close proximity to effector T cells, dormant tumor cells are not eliminated and support a CD4 + and FoxP3 + Treg-rich microenvironment.…”

Section: Senescence Within the “Equilibrium Phase”mentioning

confidence: 99%

The senescence journey in cancer immunoediting

Zingoni,

Antonangeli,

Sozzani

et al. 2024

Mol Cancer

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Cancer progression is continuously controlled by the immune system which can identify and destroy nascent tumor cells or inhibit metastatic spreading. However, the immune system and its deregulated activity in the tumor microenvironment can also promote tumor progression favoring the outgrowth of cancers capable of escaping immune control, in a process termed cancer immunoediting. This process, which has been classified into three phases, i.e. “elimination”, “equilibrium” and “escape”, is influenced by several cancer- and microenvironment-dependent factors. Senescence is a cellular program primed by cells in response to different pathophysiological stimuli, which is based on long-lasting cell cycle arrest and the secretion of numerous bioactive and inflammatory molecules. Because of this, cellular senescence is a potent immunomodulatory factor promptly recruiting immune cells and actively promoting tissue remodeling. In the context of cancer, these functions can lead to both cancer immunosurveillance and immunosuppression. In this review, the authors will discuss the role of senescence in cancer immunoediting, highlighting its context- and timing-dependent effects on the different three phases, describing how senescent cells promote immune cell recruitment for cancer cell elimination or sustain tumor microenvironment inflammation for immune escape. A potential contribution of senescent cells in cancer dormancy, as a mechanism of therapy resistance and cancer relapse, will be discussed with the final objective to unravel the immunotherapeutic implications of senescence modulation in cancer.

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Section: Senescence Within the “Equilibrium Phase”mentioning

confidence: 99%

The senescence journey in cancer immunoediting

Zingoni,

Antonangeli,

Sozzani

et al. 2024

Mol Cancer

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“…Under such conditions, tumors mimic a developmentally programmed diapause state at transcriptomic and signaling levels to overcome environmental turbulence ( 20 ). Indeed, drug-tolerant and disseminating tumor cells are, in general, notorious immune evaders that take advantage of being unnoticed by the immune radar to escape the primary sites and survive as silent perpetrators ( 21 , 22 ).…”

Section: Molecular Alterations Defining Mmrp Evolutionary Trajectorymentioning

confidence: 99%

“…IL-15 trans-presentation, TGF-β-Trap with anti-EGFR, DDR inhibitors and cancer vaccines are also under active development to overcome the outstanding challenges ( 48 , 60 , 79 – 81 ). While mechanistically compatible TILs in such scenarios may provide a milieu for immune-based interventions, other tumor intrinsic evasion strategies can still be a barrier that avert T cell-mediated attack of tumors ( 22 ). For example, perforins and granzymes are two critical polarized cytotoxic effector molecules released from activated NK and T cells.…”

Section: Mechanistic Constraints Of Mmrp Tumors and Strategies Revers...mentioning

confidence: 99%

Mismatch repair-proficient tumor footprints in the sands of immune desert: mechanistic constraints and precision platforms

Majumder,

Nataraj,

Maitreyi

et al. 2024

Front. Immunol.

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Mismatch repair proficient (MMRp) tumors of colorectal origin are one of the prevalent yet unpredictable clinical challenges. Despite earnest efforts, optimal treatment modalities have yet to emerge for this class. The poor prognosis and limited actionability of MMRp are ascribed to a low neoantigen burden and a desert-like microenvironment. This review focuses on the critical roadblocks orchestrated by an immune evasive mechanistic milieu in the context of MMRp. The low density of effector immune cells, their weak spatiotemporal underpinnings, and the high-handedness of the IL-17-TGF-β signaling are intertwined and present formidable challenges for the existing therapies. Microbiome niche decorated by Fusobacterium nucleatum alters the metabolic program to maintain an immunosuppressive state. We also highlight the evolving strategies to repolarize and reinvigorate this microenvironment. Reconstruction of anti-tumor chemokine signaling, rational drug combinations eliciting T cell activation, and reprograming the maladapted microbiome are exciting developments in this direction. Alternative vulnerability of other DNA damage repair pathways is gaining momentum. Integration of liquid biopsy and ex vivo functional platforms provide precision oncology insights. We illustrated the perspectives and changing landscape of MMRp-CRC. The emerging opportunities discussed in this review can turn the tide in favor of fighting the treatment dilemma for this elusive cancer.

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