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Tumor Heterogeneity: a Great Barrier in the Age of Cancer Immunotherapy

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Tumor Heterogeneity: a Great Barrier in the Age of Cancer Immunotherapy cancers Review Tumor Heterogeneity: A Great Barrier in the Age of Cancer Immunotherapy Nader El-Sayes 1,†, Alyssa Vito 1,† and Karen Mossman 2,* 1 Department of Biochemistry and Biomedical Sciences, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada; [email protected] (N.E.-S.); [email protected] (A.V.) 2 Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada * Correspondence: [email protected] † These authors contributed equally to this publication. Simple Summary: Despite great advances in cancer therapy, tumor heterogeneity continues to be a great barrier for the successful treatment of cancer. It has long been established that tumor heterogeneity is prevelant in most cancer patients and is a major driver of acquired resistance to all forms of cancer therapy. In the case of immunotherapy, the response of the immune system against specific tumor antigens can drive selective pressure towards antigen-negative cells, which is a common cause of relapse in the clinic. In this review we summarize the mechanisms in which tumor heterogeity can arise. Furthermore, we discuss recent advances in the field of oncology that can be used to better identify, study, and overcome tumor heterogeneity. Abstract: Throughout the history of oncology research, tumor heterogeneity has been a major hurdle for the successful treatment of cancer. As a result of aberrant changes in the tumor microenvironment such as high mutational burden, hypoxic conditions and abnormal vasculature, several malignant subpopulations often exist within a single tumor mass. Therapeutic intervention can also increase Citation: El-Sayes, N.; Vito, A.; selective pressure towards subpopulations with acquired resistance. This phenomenon is often Mossman, K. Tumor Heterogeneity: the cause of relapse in previously responsive patients, drastically changing the expected outcome A Great Barrier in the Age of Cancer Immunotherapy. Cancers 2021, 13, of therapy. In the case of cancer immunotherapy, tumor heterogeneity is a substantial barrier as 806. https://doi.org/10.3390/ acquired resistance often takes the form of antigen escape and immunosuppression. In an effort to cancers13040806 combat intrinsic resistance mechanisms, therapies are often combined as a multi-pronged approach to target multiple pathways simultaneously. These multi-therapy regimens have long been a mainstay Academic Editor: Geeta Upadhyay of clinical oncology with chemotherapy cocktails but are more recently being investigated in the Received: 26 January 2021 emerging landscape of immunotherapy. Furthermore, as high throughput technology becomes Accepted: 12 February 2021 more affordable and accessible, researchers continue to deepen their understanding of the factors Published: 15 February 2021 that influence tumor heterogeneity and shape the TME over the course of treatment regimens. In this review, we will investigate the factors that give rise to tumor heterogeneity and the impact it Publisher’s Note: MDPI stays neutral has on the field of immunotherapy. We will discuss how tumor heterogeneity causes resistance to with regard to jurisdictional claims in various treatments and review the strategies currently being employed to overcome this challenging published maps and institutional affil- clinical hurdle. Finally, we will outline areas of research that should be prioritized to gain a better iations. understanding of tumor heterogeneity and develop appropriate solutions. Keywords: tumor heterogeneity; antigen escape; immunotherapy; cancer Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article 1. Introduction distributed under the terms and conditions of the Creative Commons Major challenges with universal cancer therapy have historically been attributed to Attribution (CC BY) license (https:// the large number of subtypes of the disease and the biological differences associated with creativecommons.org/licenses/by/ cancers arising in different parts of the body. While this locational diversity remains a 4.0/). challenge for unifying cancer treatment across various types, it has now become clear that Cancers 2021, 13, 806. https://doi.org/10.3390/cancers13040806 https://www.mdpi.com/journal/cancers Cancers 2021, 13, x 2 of 14 Cancers 2021, 13, 806 2 of 14 ditions of the Creative Commons At- eveneven patientspatients withwith phenotypicallyphenotypically identicalidentical cancerscancers oftenoften havehave dichotomousdichotomous responsesresponses toto tribution (CC BY) license (http://cre- treatmenttreatment [ 1[1,2],2].. As As we we have have continued continued to investigateto investigate the the inner inner workings workings of a tumor,of a tumor, we have we ativecommons.org/licenses/by/4.0/). discoveredhave discovered that cancers that cancers are formed are formed by many by distinctmany distinct cellular cellular populations, populations, rather thanrather a homogenousthan a homogenous clusterof cluster identical of identical cells. This cells. tumor This heterogeneity tumor heterogeneity can take the can form take of the cellular form andof cellular genetic and heterogeneity. genetic heterogeneity. Cellular heterogeneity Cellular heterogeneity is used to describe is used to the describe diversity the of diver- cells thatsity canof cells be found that incan the be tumor found microenvironment in the tumor microenvironment (TME). The presence (TME). of cancer-associated The presence of fibroblasts,cancer-associated endothelial fibroblasts, cells and endothelial immune cells cells plays and animmune important cells role plays in tumor an important progression role andin tumor response progression to therapy. and In response this review, to however,therapy. In we this will review, focus on however, the genetic we heterogeneity will focus on ofthe cancer genetic cells heterogeneity within one or of several cancer tumors,cells within which one is oftenor several a driver tumors, of acquired whichresistance is often a indriver tumors of acquired and represents resistance a major in tumors hurdle and for represents proper diagnosis, a major prognostichurdle for predictionproper diagno- and therapeuticsis, prognostic efficacy prediction [3]. and therapeutic efficacy [3]. ItIt isis wellwell establishedestablished thatthat tumortumor heterogeneityheterogeneity isis largelylargely drivendriven byby aberrantaberrant changeschanges inin thethe TME,TME, suchsuch asas highhigh mutationalmutational burden,burden, hypoxichypoxic conditionsconditions andand abnormalabnormal vascula-vascula- tureture [[4]4].. Additionally,Additionally, native native TME TME factors factors aside, aside, the the administration administration of of therapy therapy can can result result in selectivein selective pressure pressure towards towards subpopulations subpopulations with with acquired acquired resistance resistance mechanisms mechanisms [3,5]. [3,5] This. phenomenonThis phenomenon is often is often the cause the cause of relapse of relapse in previously in previously responsive responsive patients, patients, drastically drasti- shiftingcally shifting expected expected therapeutic therapeutic outcomes. outcomes. As oncology As oncology research research has progressed has progressed and evolved, and soevolved, too has so our too understanding has our understanding of cancer biologyof cancer and biology the immunological and the immunological synapse involved synapse ininvolved swaying in clinicalswaying prognoses. clinical prognoses. But the question But the question still remains, still remains how do, thesehow do environmen- these envi- talronmental and therapeutic and therapeutic situations situations influencing influencing the tumor the create tumor heterogeneity create heterogeneity and distinctive and dis- cellulartinctive populations?cellular populations? InIn 19761976 PeterPeter NowellNowell publishedpublished aa landmarklandmark perspectiveperspective piecepiece suggestingsuggesting thatthat cancercancer arisesarises through an an evolutionary evolutionary proc process,ess, similar similar in innature nature to Darwinian to Darwinian evolution evolution and andnat- naturalural selection selection [6]. [Nowell6]. Nowell suggested suggested that cancers that cancers arise through arise through stepwise, stepwise, somatic somatic cellular cellularmutations mutations inevitably inevitably leading to leading multiple to multiplesub-clonal sub-clonal populations populations (Figure 1) (Figure. This revelation1). This revelationchanged the changed way that the waycancer that was cancer studied was studiedand further and furtherhighlighted highlighted the need the for need multi for- multi-prongedpronged therapeutic therapeutic approaches approaches and a anddeeper a deeper understanding understanding of cancer of cancer at a genomic at a genomic level. level.Indeed, Indeed, as therapeutic as therapeutic approaches approaches have evolved have evolved in recent in recentdecades, decades, we have we seen have an seen in- ansurgence insurgence of combined of combined therapeutic therapeutic modalities modalities that can that target can cancer target cells cancer through cells throughdiffering differingmechanisms, mechanisms, with the withgoal of the overcoming goal of overcoming innate acquired innate acquiredresistance. resistance. FigureFigure 1.1. ClonalClonal evolutionevolution andand developmentdevelopment ofof tumortumor heterogeneity.heterogeneity see correct label positioning
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