Ludwig Center for Metastasis Research: The Role of Immunology in Radiotherapy

Radiotherapy has long been considered a successful treatment option for localized tumors; however, recent data suggests that radiotherapy may activate the immune system and that the combination of radiotherapy and immune therapies may have the potential to improve both local and distant control of tumor deposits.

At the Ludwig Center, we have explored the basis of treatment strategies for patients with locally advanced or distant metastasis. These patients generally receive prolonged treatment with chemotherapy or palliative fractionated radiotherapy. Despite initial response, treatment resistance frequently develops and a cure in these situations is uncommon. Because of technological advances, we can now treat some of these clinically advanced patients with high-dose, or ablative, radiotherapy with limited damage to the normal surrounding  tissues Surprisingly we found that some of the anti-tumor effects of radiotherapy are dependent on T cell responses. Ablative radiotherapy (high dose) increases T cell priming in draining lymphoid tissues, leading to the reduction or eradication of the tumor or metastasis in CD8(+) T cell-dependent fashion. Furthermore, we discovered that ablative radiotherapy-initiated immune response is lessened by the use of conventional fractionated radiotherapy or chemotherapy, but amplified by local immunotherapy. This study challenges current methods of treatment for metastasis and emphasizes the importance of immunotherapy in preventing relapse. We have conducted several investigations in order to more fully understand the mechanism of combined radio- and immunotherapies.  Targeting cancer cells and the adjacent stromal cells, which also present the tumor antigen, can lead to complete destruction of tumors by adoptively transferring tumor antigen-specific cytotoxic T lymphocytes. If, on the other hand, the cancer cells express low levels of the tumor antigen, the stromal cells will not be destroyed and the tumor escapes destruction. Also, we discovered that by treating these tumors expressing low levels of tumor antigen with irradiation or chemotherapy, a sufficient amount of tumor antigen is released to sensitive stromal cells for destruction by cytotoxic T lymphocytes. This work was performed in collaboration with the Spiotto, Schreiber and Fu laboratories in the Departments of Immunology and Pathology

In another study, we describe the role of type I interferon in local radiotherapy-mediated tumor control. We observed that ablative radiotherapy increased intratumoral production of type I interferon and that the antitumor effects of radiotherapy are absent in type 1 interferon nonresponsive hosts. The major target of radiotherapy-induced type I interferon is the hematopoietic compartment, or the location of blood cell production. Radiotherapy dramatically increases the cross-priming capacity of tumor-infiltrating dendritic cells, or the immune cells that process antigen material on the surface of cells, from wild-type mice, but not type I interferon receptor-deficient mice. The enhanced cross-priming capabilities depended on autocrine production of type I interferon. By using adenoviral-mediated expression of type I interferon, we demonstrated that delivery of externally produced type I interferon into the tumor tissue in the absence of radiotherapy is also sufficient to selectively expand antigen-specific T cells, leading to complete tumor regression. Our study reveals that local high-dose radiotherapy can trigger the production of type I interferon that initiates a cascading innate and adaptive immune response. The cell autonomous effects of interferon on tumor cells are described in a separate section. This work was performed in collaboration with the Fu lab.

In studies to improve the immune activating effects of radiotherapy, we employed experimental melanoma and pancreatic carcinoma.   We found that a treatment combining radiotherapy with the drug Velparib was an effective method of inhibiting poly (ADP-ribose) polymerase inhibitor (PARPi), limiting DNA repair and promoting premature cell senescence.  Work described above demonstrated that cytotoxic T lymphocytes help mediate the effects of radiotherapy. In this study, we discovered that senescent tumor cells express immunostimulatory cytokines, which activate and attract the T lymphocytes. This process creates an effective antitumor response. When these senescent tumor cells were injected into tumor-bearing mice, a “vaccine” effect was produced which inhibited tumor growth distant from the site of vaccination and markedly improved the anti-tumor effects of radiotherapy.  This work was carried out in collaboration with the Kron lab in the Department of Molecular Genetics and Cell Biology  

CURRENT WORK  

 We are currently working with the Fu lab to produce a vaccine against papilloma virus and with the Kron lab to produce an effective senescent cell vaccine. We are also collaborating with the Fu lab on studies of the tumor microenvironment to investigate how radiation might alleviate tumor immunosuppression and how radiotherapy can best be integrated with blocking antibodies to PD-1 (programmed cell death protein 1) and its ligand PD-L1. PD-1 inhibits T cell function and its inhibition is reported to enhance the effector phase of T cell function.  We are also collaborating with the Wolchak laboratory at the Memorial Sloan-Kettering Cancer Center Ludwig Center to study the effect of OX86, an agonistic antibody to OX40, in combination with radiotherapy. OX 40 is expressed on T cells and enhances both the priming and effector phases of T cell function. In addition we are working with the Yamini laboratory in the Department of Surgery to define the role of the p50 subunit of NFkB, an important immune effector transcription factor in DNA repair

REFERENCES

Barreto-Andrade JC, Efimova EV, Mauceri HJ, Beckett MA, Sutton HG, Darga TE, Vokes EE, Posner MC, Kron SJ, Weichselbaum RR. Response of human prostate cancer cells and tumors to combining PARP inhibition with ionizing radiation. Mol Cancer Ther. 2011 Jul; 10 (7) :1185-93. PubMed PMID:21571912; PubMed Central PMCID: PMC3140695.

Burnette B, Fu YX, Weichselbaum RR. The confluence of radiotherapy and immunotherapy. Front Oncol. 2012; 2:143. PubMed PMID:23087904; PubMed Central PMCID: PMC3472545.

Burnette BC, Liang H, Lee Y, Chlewicki L, Khodarev NN, Weichselbaum RR, Fu YX, Auh SL. The efficacy of radiotherapy relies upon induction of type i interferon-dependent innate and adaptive immunity. Cancer Res. 2011 Apr 1; 71 (7) :2488-96. PubMed PMID:21300764; PubMed Central PMCID: PMC3070872.

Efimova EV, Mauceri HJ, Golden DW, Labay E, Bindokas VP, Darga TE, Chakraborty C, Barreto-Andrade JC, Crawley C, Sutton HG, Kron SJ, Weichselbaum RR. Poly(ADP-ribose) polymerase inhibitor induces accelerated senescence in irradiated breast cancer cells and tumors. Cancer Res. 2010 Aug 1; 70 (15) :6277-82. PubMed PMID:20610628; PubMed Central PMCID: PMC2912962.

Lee Y, Auh SL, Wang Y, Burnette B, Wang Y, Meng Y, Beckett M, Sharma R, Chin R, Tu T, Weichselbaum RR, Fu YX. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood. 2009 Jul 16; 114 (3) :589-95. PubMed PMID:19349616; PubMed Central PMCID: PMC2713472.

Meng Y, Efimova EV, Hamzeh KW, Darga TE, Mauceri HJ, Fu YX, Kron SJ, Weichselbaum RR. Radiation-inducible immunotherapy for cancer: senescent tumor cells as a cancer vaccine. Mol Ther. 2012 May; 20 (5) :1046-55. PubMed PMID:22334019; PubMed Central PMCID: PMC3345982.

Meng Y, Mauceri HJ, Khodarev NN, Darga TE, Pitroda SP, Beckett MA, Kufe DW, Weichselbaum RR. AdEgr-TNF and local ionizing radiation suppress metastases by interferon-beta-dependent activation of antigen-specific CD8+ T cells. Mol Ther. 2010 May; 18 (5) :912-20. PubMed PMID:20197756; PubMed Central PMCID: PMC2890103.

Schmitt AM, Crawley CD, Kang S, Raleigh DR, Yu X, Wahlstrom JS, Voce DJ, Darga TE, Weichselbaum RR, Yamini B. p50 (NF-κB1) is an effector protein in the cytotoxic response to DNA methylation damage. Mol Cell. 2011 Dec 9; 44 (5) :785-96. PubMed PMID:22152481; PubMed Central PMCID: PMC3240852.

Schreiber K, Arina A, Engels B, Spiotto MT, Sidney J, Sette A, Karrison TG, Weichselbaum RR, Rowley DA, Schreiber H. Spleen cells from young but not old immunized mice eradicate large established cancers. Clin Cancer Res. 2012 May 1; 18 (9) :2526-33. PubMed PMID:22415314.

Wu TH, Schreiber K, Arina A, Khodarev NN, Efimova EV, Rowley DA, Weichselbaum RR, Schreiber H. Progression of cancer from indolent to aggressive despite antigen retention and increased expression of interferon-gamma inducible genes. Cancer Immun. 2011 Jun 30; 11:2. PubMed PMID:21714479; PubMed Central PMCID: PMC3127375.

Zhang B, Bowerman NA, Salama JK, Schmidt H, Spiotto MT, Schietinger A, Yu P, Fu YX, Weichselbaum RR, Rowley DA, Kranz DM, Schreiber H. Induced sensitization of tumor stroma leads to eradication of established cancer by T cells. J Exp Med. 2007 Jan 22; 204 (1) :49-55. PubMed PMID:17210731; PubMed Central PMCID: PMC2118433.