Combination of Id2 Knockdown Whole Tumor Cells and Checkpoint Blockade: A Potent Vaccine Strategy in a Mouse Neuroblastoma Model

Abstract

Tumor vaccines have held much promise, but to date have demonstrated little clinical success. This lack of success is conceivably due to poor tumor antigen presentation combined with immuno-suppressive mechanisms exploited by the tumor itself. Knock down of Inhibitor of differentiation protein 2 (Id2-kd) in mouse neuroblastoma whole tumor cells rendered these cells immunogenic. Id2-kd neuroblastoma (Neuro2a) cells (Id2-kd N2a) failed to grow in most immune competent mice and these mice subsequently developed immunity against further wild-type Neuro2a tumor cell challenge. Id2-kd N2a cells grew aggressively in immune-compromised hosts, thereby establishing the immunogenicity of these cells. Therapeutic vaccination with Id2-kd N2a cells alone suppressed tumor growth even in established neuroblastoma tumors and when used in combination with immune checkpoint blockade eradicated large established tumors. Mechanistically, immune cell depletion studies demonstrated that while CD8+ T cells are critical for antitumor immunity, CD4+ T cells are also required to induce a sustained long-lasting helper effect. An increase in number of CD8+ T-cells and enhanced production of interferon gamma (IFNγ) was observed in tumor antigen stimulated splenocytes of vaccinated mice. More importantly, a massive influx of cytotoxic CD8+ T-cells infiltrated the shrinking tumor following combined immunotherapy. These findings show that down regulation of Id2 induced tumor cell immunity and in combination with checkpoint blockade produced a novel, potent, T-cell mediated tumor vaccine strategy.

MYCN Amplification Is Associated with Repressed Cellular Immunity in Neuroblastoma: An In Silico Immunological Analysis of TARGET Database

“…Indirect evidence is observed in the opsoclonus–myoclonus syndrome associated with low or intermediate stage NB. These tumors have profound T-cell infiltrates and are not MYCN amplified ( 21 – 23 ). The OMS phenomenon is thought to be an autoimmune effect and along with NB that spontaneously regresses this tumor may be an ideal model for studying and understanding tumor immunity as it relates to tumor biology and prognosis.…”

STAT3-blocked whole-cell hepatoma vaccine induces cellular and humoral immune response against HCC

“…Tumor cells can directly escape from T-cell recognition by downregulating MHC class I but upregulating surface ligands, such as PD-L1, CTLA-4, and certain other ligands of inhibitory T-cell receptors, which mediate T-cell exhaustion [ 20 , 29 , 30 ]. Chakrabarti demonstrated that an attenuated Id2-kd whole-cell neuroblastoma vaccine was safe in mice and could induce a broad tumor-specific cellular immunity, which protected against tumor formation in prophylactic tumor models and eradicated large established neuroblastoma tumors in combination with an anti-CTLA-4 antibody [ 31 ]. A recent study showed that the IL-27/STAT3 axis induced the expression of PD-L1/2, and that STAT3 blockage reversed T cell exhaustion [ 32 ].…”

Photothermal Therapy Generates a Thermal Window of Immunogenic Cell Death in Neuroblastoma

“…A) Expression of ICD markers as a function of thermal dose described in terms of cumulative equivalent minutes at 43 °C; a thermal dose parameter (CEM43). [38] The grey shaded area represents the region of increased ICD elicited by PBNP-PTT. B) % Survival of mice (at 100 d) challenged with Neuro2a tumors that were vaccinated with PBNP-PTT-treated Neuro2a cells.…”

“…PBNP‐PTT‐treated Neuro2a cells exhibit a thermal “window” of ICD, which is associated with improved protection against tumor challenge. A) Expression of ICD markers as a function of thermal dose described in terms of cumulative equivalent minutes at 43 °C; a thermal dose parameter (CEM43) . The grey shaded area represents the region of increased ICD elicited by PBNP‐PTT.…”