5-Aza-2′-deoxycytidine potentiates antitumour immune response induced by photodynamic therapy

Abstract

Photodynamic therapy (PDT) of tumours is based on administration of a photosensitiser followed by irradiation of the tumour with visible light leading to production of reactive oxygen species that cause direct tumour cell death and vascular damage. PDT also initiates acute local inflammation, which facilitates the development of adaptive antitumour immunity. It has recently been reported that PDT can induce strong antitumour immunity towards tumours cells expressing P1A, tumour-associated antigen. Using four different tumour models, we show that antitumour immune response can be further improved when PDT is combined with a clinically approved epigenetic agent that induces expression of a silenced P1A antigen. Induction of P1A with 5-aza-2′-deoxycytidine, a methyltransferase inhibitor, resulted in potentiated antitumour effects in mice with Lewis lung carcinoma and 4T1 mammary carcinoma when combined with PDT treatment. In CT26 colon carcinoma and EMT6 mammary carcinoma models the combination therapy resulted in complete responses and long-term survival. All long-term surviving mice were resistant to re-inoculation with the same tumour cells. Antitumour efficacy of the combination treatment was severely impaired by depletion of CD8+ cytotoxic T cells, whereas adoptive transfer of CD8+ T cells from long-term surviving mice allowed for significant tumour growth delay in tumour-bearing mice. Taken together, these findings show that PDT leads to strong specific antitumour immune responses, and that epigenetic modification of tumour antigens levels may be a novel approach to further enhance the effectiveness of PDT. The present results provide a strong rationale for clinical development of this therapeutic approach.

Elimination of primary tumours and control of metastasis with rationally designed bacteriochlorin photodynamic therapy regimens

“…Various authors reported systemic PDT-induced anti-tumour immune responses [22][23][24][25], including cases of vascular-PDT of BALB/c mice bearing CT26 tumours when verteporfin [26] or Pd-bacteriopheophorbide WST11 [21] were used. However, PDT with verteporfin failed to cure in mice bearing wild-type CT26 tumours.…”

Antitumor Immunity Triggered by Melphalan Is Potentiated by Melanoma Cell Surface–Associated Calreticulin

“…After 10 days, mice were rechallenged with untreated B78 cells into the right flank (50 Â 10 3 cells in 100 mL PBS) and tumor growth was monitored for the next 40 days. Depletion of CD4 þ or CD8 þ T cells was performed according to the previously described protocol (30).…”

Alphavirus-Based Vaccines in Melanoma: Rationale and Potential Improvements in Immunotherapeutic Combinations

“…Treatment with 5-aza-2′-deoxycitidine restored expression of CTAs and IFN signature genes in mouse and human melanomas, thus sensitizing [94,95]. As another example, 5-aza-2′-deoxycitidine was found to potentiate the immunerelated and antitumor effects of photodynamic therapy, which is based on administration of a photosensitizer and ionizing radiation [96]. These initial observations suggest that DMT inhibitors may constitute valid candidate treatments to be combined with antimelanoma vaccines.…”