Rejection of immunogenic tumor clones is limited by clonal fraction

Gejman, Ron S.; Chang, Amy; Jones, Heather F.; DiKun, Krysta; Hakimi, A. Ari; Schietinger, Andrea; Scheinberg, David A.

doi:10.7554/elife.41090

Cited by 111 publications

(110 citation statements)

References 54 publications

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“…The former due to an evolution following effectively-neutral dynamics, and the latter because strong depletion leads to an insufficient number of disadvantageous mutations. However, recent evidence suggests that mutations present in a low proportion of cells might not elicit an immune response depending on the characteristics of the arising neopeptides 47 , and we expect this effect to be reinforced in tumours with complex spatial architecture such as colorectal cancer which allows cancer cells to 'hide' from the immune system. This means that negative selection only operates on larger clones -and we note that potentially this shift from neutral to negatively-selected dynamics could be detected with very high depth sequencing or over a sufficient cohort of cancer cases.…”

Section: Discussionmentioning

confidence: 93%

Evolutionary dynamics of neoantigens in growing tumours

Lakatos

Williams

Schenck

et al. 2019

Preprint

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Cancer evolution is driven by the acquisition of somatic mutations that provide cells with a beneficial phenotype in a changing microenvironment. However, mutations that give rise to neoantigens, novel cancer-specific peptides that elicit an immune response, are likely to be disadvantageous. Here we show how the clonal structure and immunogenotype of growing tumours is shaped by negative selection in response to neoantigenic mutations. We construct a mathematical model of neoantigen evolution in a growing tumour, and verify the model using genomic sequencing data. The model predicts that, in the absence of active immune escape mechanisms, tumours either evolve clonal neoantigens (antigen-'hot'), or have no clonally-expanded neoantigens at all (antigen-'cold'), whereas antigen-'warm' tumours (with high frequency subclonal neoantigens) form only following the evolution of immune evasion. Counterintuitively, strong negative selection for neoantigens during tumour formation leads to an increased number of antigen-warm or -hot tumours, as a consequence of selective pressure for immune escape. Further, we show that the clone size distribution under negative selection is effectively-neutral, and moreover, that stronger negative selection paradoxically leads to more neutral-like dynamics. Analysis of antigen clone sizes and immune escape in colorectal cancer exome sequencing data confirms these results.Overall, we provide and verify a mathematical framework to understand the evolutionary dynamics and clonality of neoantigens in human cancers that may inform patientspecific immunotherapy decision-making.

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Section: Discussionmentioning

confidence: 93%

Evolutionary dynamics of neoantigens in growing tumours

Lakatos

Williams

Schenck

et al. 2019

Preprint

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“…For neoantigens, intra‐ and inter‐tumoral genetic heterogeneity can lead to this form of resistance, especially when the targeted antigens are derived from passenger mutations. The presence of a significant proportion of genetic subclones within a tumor mass leads to a loss of T cell‐mediated anti‐tumor efficacy in mice . Similarly, genetic clonal heterogeneity is associated with a lack of treatment efficacy to immune checkpoint inhibitors in humans .…”

Section: Therapeutic Resistance To Tcr‐based Cancer Immunotherapiesmentioning

confidence: 99%

“…The presence of a significant proportion of genetic subclones within a tumor mass leads to a loss of T cell-mediated antitumor efficacy in mice. 236 Similarly, genetic clonal heterogeneity is associated with a lack of treatment efficacy to immune checkpoint inhibitors in humans. 204 Heterogeneity in the epigenetic landscape of cancer cells, 237 DNA methyl-transferase inhibitors and other epigenetic modifiers, including histone deacetylase inhibitors, can increase CGA expression in cancer cells but not fibroblasts in vitro.…”

Section: Primary T Cell-extrinsic Resistancementioning

confidence: 99%

T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

Chandran

Klebanoff

2019

Immunological Reviews

237

185

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Adoptive cell transfer (ACT) using chimeric antigen receptor (CAR)‐modified T cells can induce durable remissions in patients with refractory B‐lymphoid cancers. By contrast, results applying CAR‐modified T cells to solid malignancies have been comparatively modest. Alternative strategies to redirect T cell specificity and cytolytic function are therefore necessary if ACT is to serve a greater role in human cancer treatments. T cell receptors (TCRs) are antigen recognition structures physiologically expressed by all T cells that have complementary, and in some cases superior, properties to CARs. Unlike CARs, TCRs confer recognition to epitopes derived from proteins residing within any subcellular compartment, including the membrane, cytoplasm and nucleus. This enables TCRs to detect a broad universe of targets, such as neoantigens, cancer germline antigens, and viral oncoproteins. Moreover, because TCRs have evolved to efficiently detect and amplify antigenic signals, these receptors respond to epitope densities many fold smaller than required for CAR‐signaling. Herein, we summarize recent clinical data demonstrating that TCR‐based immunotherapies can mediate regression of solid malignancies, including immune‐checkpoint inhibitor refractory cancers. These trials simultaneously highlight emerging mechanisms of TCR resistance. We conclude by discussing how TCR‐based immunotherapies can achieve broader dissemination through innovations in cell manufacturing and non‐viral genome integration techniques.

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“…These results suggest that while the strength of tumor antigenicity is critical in determining fit to be a prospective neoantigen, it is also vital to consider the abundance of the neoantigen, as even a small percentage of cells not expressing neoantigens can escape, and outgrow, a phenomenon that is described as immunoediting 30 . A recent study had also shown that the rejection of immunogenic clones within tumors is dependent on the fractional abundance of the subclone, as well as the nature of the antigen 13 .…”

Section: When Animals Were Inoculated With Combinations Of Ova + and mentioning

confidence: 99%

“…The exact percentage of cells bearing T cells specific for any given neoantigen is a fraction of the total T cell repertoire, which is why we often see cancer vaccines are designed to target multiple neoantigens to be effective before immune response diversification by epitope spreading 4,11,12 . However, previous works have also shown that immune system is capable of selective recognizing and depleting immunogenic subclones in a predominantly nonimmunogenic tumor 13 .…”

Section: Introductionmentioning

confidence: 99%

Tumor neoantigen heterogeneity impacts bystander immune inhibition of pancreatic cancer growth

Das

Zhou

Liu

et al. 2020

Preprint

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The threshold for immunogenic clonal fraction in a heterogeneous solid tumor required to induce effective bystander killing of non-immunogenic subclones is unknown. Pancreatic cancer poses crucial challenges for immune therapeutic interventions due to low mutational burden and consequent lack of neoantigens. Here, we designed a model to incorporate artificial neoantigens into genes of interest in cancer cells and to test the potential of said antigens to actuate bystander killing. By precisely controlling the abundance of a neoantigen in the tumor, we studied the impact of neoantigen frequency on immune response and immune escape. Our results showed that a single, strong, widely expressed neoantigen could lead to a robust antitumor response when at least 80% of cancer cells express the neoantigen. Further, immunological assays revealed induction of T-cell responses against a non-target self-antigen on KRAS oncoprotein, when we inoculated animals with a high frequency of tumor cells expressing a test neoantigen. Using nanoparticle-based gene therapy, we successfully altered the tumor microenvironment by perturbing interleukin-12 and interleukin-10 gene expression. The subsequent remodeling of the microenvironment reduced the threshold of neoantigen frequency at which bioluminescent signal intensity for tumor burden decreased 1.5-logfold, marking a robust tumor growth inhibition, from 83% to as low as 29%. Our results thus suggest that bystander killing is rather inefficient in immunologically cold tumors like pancreatic cancer and requires an extremely high abundance of neoantigens. However, the bystander killing mediated antitumor response can be rescued, when supported by adjuvant immune therapy.

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Rejection of immunogenic tumor clones is limited by clonal fraction

Cited by 111 publications

References 54 publications

Evolutionary dynamics of neoantigens in growing tumours

Evolutionary dynamics of neoantigens in growing tumours

T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

Tumor neoantigen heterogeneity impacts bystander immune inhibition of pancreatic cancer growth

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