Overcoming Immune System Evasion by Personalized Immunotherapy

Kevin C Soares; Lei Zheng; Nita Ahuja

Disclosures

Personalized Medicine. 2014;11(6):561-564. 

In This Article

Personalized Evasion Mechanisms

Immune system surveillance is a critical component that suppresses tumor cell propagation by tumor cell lysis or directly inhibiting its ability to grow or metastasize. However, the immune system can facilitate tumor growth by selecting for cells more likely to survive and conditioning the tumor microenvironment for tumor survival and outgrowth.[3] This process, termed immune editing, places a strong selection pressure on the tumors and is described in three phases: elimination, equilibrium and escape. During the elimination phase, natural killer cells and dendritic cells, which travel to nearby lymph nodes and activate tumor-specific CD4+ and CD8+ T cells, work in conjunction to eliminate nascent tumors.[3] Subsequently, tumor cells are eliminated via activated cytotoxic T cells during the equilibrium phase. During this phase, however, resistant tumor cells are selected out by evading immune system detection depending on the mutations acquired during carcinogenesis.[3] The equilibrium phase continues as long as the immune system is able to eliminate tumor cells. Eventually, this process is exhausted. The remaining tumor cells evade immune system detection due to alterations in cell death pathways, acquisition of stem cell-like phenotypes, epigenetic transformation as well as downregulated antigen presentation.[4]

Importantly, genetically unstable tumor cells are able to circumvent the selective pressure of immune surveillance and proceed to the escape phase. However, increased mutations within a tumor may also lead to expression of neoantigens rendering them more susceptible to targeted immunotherapies. For example, microsatellite unstable colon cancer tumors have been associated with increased infiltrating T-cell populations and a better prognosis compared with microsatellite stable colon cancer secondary to increased neoantigens as a result of defects in DNA mismatch repair genes.[5] Antigen-specific vaccines targeting known tumor antigens have been tested in multiple clinical trials but with limited success.[6] Ascertaining which tumor antigens are abundantly expressed and critical to tumor disease progression is an important component of personalized vaccine therapy. Genetic characterization of tumor cells and identification of these neoantigens allows for the development of individualized mutagen-specific vaccines.

Our group has recently reported novel intratumoral lymphoid aggregates in pancreatic tumors after neoadjuvant whole-cell allogeneic GM-CSF vaccine therapy.[7] The genetic characterization of these tertiary lymphoid aggregates demonstrated upregulation of immunosuppressive regulatory immune mechanisms including PD-1, PD-L1 and the regulatory T-cell pathway.[7] Our preclinical data indicates that the combination of vaccine therapy with PD-1 or PD-L1 blockade in pancreatic cancer improves vaccine therapy by facilitating effector T-cell infiltration into the tumor microenvironment [SOARES KC ET AL., UNPUBLISHED DATA]. As a result, gene signatures from these lymphoid aggregates can potentially be used to direct vaccine therapy with a personalized immune modulator.

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