Immune Evasion Colorectal Cancer

Published OnlineFirst May 7, 2015; DOI: 10.1158/2159-8290.CD-RW2015-086

RESEARCH WATCH

Colorectal Cancer

Major finding: TP53 loss coincides Clinical relevance: α-amanitin antibody– Impact: Antitumor therapy targeting with hemizygous POLR2A deletion, drug conjugates inhibit the growth of POLR2A may prove effective in a sensitizing cells to POLR2A inhibition. tumors with hemizygous POLR2A loss. broad range of cancers.

TP53 LOSS CREATES SUSCEPTIBILITY TO ANTI–POL II THERAPY IN COLORECTAL CANCER Genetic perturbation of the tumor suppressor TP53 status. In addition, inhibition of POLR2A gene TP53 is one of the most common events in specifi cally enhanced the cytotoxic effects of stand- human carcinogenesis; however, efforts to reac- ard chemotherapeutics in POLR2Aloss cells. This tivate p53 have thus far been unsuccessful. Liu sensitivity to POLR2A inhibition was recapitulated and colleagues hypothesized that hemizygous dele- in vivo using siRNA-mediated POLR2A knock- tion of the chromosome 17p13 region harboring down, which selectively suppressed the growth of TP53 also encompasses neighboring genes required for cell established POLR2Aloss xenograft tumors. Furthermore, low- survival, and found that POLR2A, which encodes the largest dose treatment with an α-amanitin–based antibody–drug subunit of RNA polymerase II (Pol II), is commonly code- conjugate targeting epithelial cell adhesion molecule, which leted with TP53 in human colorectal cancer. Hemizygous loss exhibits increased effi cacy and reduced toxicity compared of POLR2A was tightly associated with decreased POLR2A with α-amanitin, induced complete regression of POLR2Aloss expression and rendered cells susceptible to inhibition of tumors, but not POLR2Aneutral tumors, in an orthotopic model POLR2A. Treatment of colorectal cancer cell lines with low of human colorectal cancer. Overall, these observations sup- doses of the specifi c PO LR2A inhibitor α-amanitin or shRNA- port the hypothesis that collateral loss of POLR2A due to TP53 mediated knockdown of POLR2A resulted in decreased prolif- deletion renders cells susceptible to α-amanitin therapy and eration and induction of cell death in cells with hemizygous suggest that this therapeutic strategy may be broadly applied POLR2A deletion (POLR2Aloss), but only modestly affected across cancer types. ■ POLR2Aneutral cells. Consistent with these fi ndings, exogenous expression of POLR2A in POLR2Aloss cells rescued resist- Liu Y, Zhang X, Han C, Wan G, Huang X, Ivan C, et al. TP53 ance to α-amanitin, whereas hemizygous deletion of POLR2A loss creates therapeutic vulnerability in colorectal cancer. Nature sensitized POL2RAneutral cells to α-amanitin independent of 2015;520:697–701.

Immune Evasion

Major finding: IgA+IL10+PD-L1+ plasma Clinical relevance: B cells are more prev- Impact: Elimination or blockade of cells suppress oxaliplatin-induced T-cell alent in refractory and metastatic human tumor-infiltrating plasmocytes may activation in prostate cancer models. prostate tumors than early tumors. potentiate immunogenic chemotherapy.

B CELLS CAN SUPPRESS CHEMOTHERAPY-INDUCED IMMUNOGENIC CELL DEATH Some chemotherapeutic agents, such as oxaliplatin, a similar IgA+ B-cell population could be detected in human platinum-based compound that is being investigated as a prostate cancer samples, with a higher level of IgA+ plasmo- potential prostate cancer therapy, stimulate immunogenic cytes and lower frequency of CTLs in treatment-resistant cell death and activate cytotoxic T lymphocytes (CTL). Sha- and metastatic tumor samples compared with early tumors, lapour and colleagues found that tumors arising in inde- suggesting that an immunosuppressive B-cell population pendent mouse models of prostate cancer ultimately became may also promote tumor progression and immune evasion resistant to oxaliplatin in association with increased levels in human prostate cancer and possibly represent an attrac- of tumor-infi ltrating IgA+ plasmocytic B cells. A large subset tive therapeutic target. These fi ndings also raise the possibil- of the tumor-infi ltrating IgA+ B-cell population expressed ity that inhibition or elimination of tumor-infi ltrating IgA+ IL10 and PD-L1, which have both been implicated in T-cell plasmocytes may increase antitumor immune responses and anergy and exhaustion. Oxaliplatin resistance could be over- subsequently augment the activity of immunogenic chemo- come and CTL-dependent tumor regression could be induced therapy alone or in combination with immunotherapy, espe- by genetic or pharmacologic B-cell depletion or by specifi - cially in diseases such as prostate cancer that do not respond cally blocking the generation of the immunosuppressive IgA+ to single immune checkpoint inhibitor therapies. ■ plasmocytes through inhibition of TGFβR2 signaling. B-cell depletion or inhibition of TGFβR2-dependent IgA+ plasmo- Shalapour S, Font-Burgada J, Di Caro G, Zhong Z, Sanchez-Lopez cyte generation also enhanced the effectiveness of adoptive E, Dhar D, et al. Immunosuppressive plasma cells impede T-cell- T-cell transfer in combination with oxaliplatin. Notably, a dependent immunogenic chemotherapy. Nature 2015;521:94–8.

Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.

JUNE 2015CANCER DISCOVERY | 577

B Cells Can Suppress Chemotherapy-Induced Immunogenic Cell Death

Cancer Discovery 2015;5:577. Published OnlineFirst May 7, 2015.

Updated version Access the most recent version of this article at: doi:10.1158/2159-8290.CD-RW2015-086

E-mail alerts Sign up to receive free email-alerts related to this article or journal.

Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at Subscriptions [email protected].

Permissions To request permission to re-use all or part of this article, use this link http://cancerdiscovery.aacrjournals.org/content/5/6/577.2. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.