Exogenous sickle erythrocytes combined with vascular disruption trigger disseminated tumor vaso-occlusion and lung tumor regression
Chiao-Wang Sun, Li-Chen Wu, Mamta Wankhede, Dezhi Wang, Jutta Thoerner, Lawrence Woody, Brian S. Sorg, Tim M. Townes, David S. Terman
Chiao-Wang Sun, Li-Chen Wu, Mamta Wankhede, Dezhi Wang, Jutta Thoerner, Lawrence Woody, Brian S. Sorg, Tim M. Townes, David S. Terman
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Research Article Hematology Oncology

Exogenous sickle erythrocytes combined with vascular disruption trigger disseminated tumor vaso-occlusion and lung tumor regression

Abstract

Hypoxic tumor niches are chief causes of treatment resistance and tumor recurrence. Sickle erythrocytes’ (SSRBCs’) intrinsic oxygen-sensing functionality empowers them to access such hypoxic niches wherein they form microaggregates that induce focal vessel closure. In search of measures to augment the scale of SSRBC-mediated tumor vaso-occlusion, we turned to the vascular disrupting agent, combretastatin A-4 (CA-4). CA-4 induces selective tumor endothelial injury, blood stasis, and hypoxia but fails to eliminate peripheral tumor foci. In this article, we show that introducing deoxygenated SSRBCs into tumor microvessels treated with CA-4 and sublethal radiation (SR) produces a massive surge of tumor vaso-occlusion and broadly propagated tumor infarctions that engulfs treatment-resistant hypoxic niches and eradicates established lung tumors. Tumor regression was histologically corroborated by significant treatment effect. Treated tumors displayed disseminated microvessels occluded by tightly packed SSRBCs along with widely distributed pimidazole-positive hypoxic tumor cells. Humanized HbS-knockin mice (SSKI) but not HbA-knockin mice (AAKI) showed a similar treatment response underscoring SSRBCs as the paramount tumoricidal effectors. Thus, CA-4-SR–remodeled tumor vessels license SSRBCs to produce an unprecedented surge of tumor vaso-occlusion and infarction that envelops treatment-resistant tumor niches resulting in complete tumor regression. Strategically deployed, these innovative tools constitute a major conceptual advance with compelling translational potential.

Authors

Chiao-Wang Sun, Li-Chen Wu, Mamta Wankhede, Dezhi Wang, Jutta Thoerner, Lawrence Woody, Brian S. Sorg, Tim M. Townes, David S. Terman

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Figure 3

Histopathology and quanfication of vaso-occlusion in sections of LLC in C57BL/6J mice obtained on day 14 after treatment with tumor SR (10 Gy) on day 12 followed by CA-4 plus passive infusion of SSRBC or AARBC on day 13.

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Histopathology and quanfication of vaso-occlusion in sections of LLC in ...
Tumor sections from mice receiving SSRBC-based triple therapy shows (A) disseminated tumor vaso-occlusion, adjacent tumor cell necrosis, and mononuclear cell infiltration (original magnification, ×10); (B) clustered tumor vessel occlusions surrounded by mononuclear cells (original magnification, ×25); (C) tumor vessels with tightly packed sickle cells (original magnification, ×40). (D) Shows extensive vaso-occlusion with mononuclear cell infiltration engulfing the tumor periphery (original magnification, ×25). (E) Demonstrates that the number of occluded tumor microvessels after treatment with SSRBC-based triple therapy exceeded that of similar AARBC-based triple therapy (**P = 0.00009) and all dual and single treatments (*P ≤ 0.0001, 2-tailed Student’s t test; n = 3). Tumor vaso-occlusion was quantified in tumor sections by enumerating the total number of occluded microvessels in 40 fields at ×40 original magnification. Microvessels were considered occluded when at least 80% of the vessel lumen was filled with erythrocytes.